diagnosis and importance of viral respiratory tract infections in children m. ieven vakb leuven 08....
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Diagnosis and importance of viral
respiratory tract infections in children
M. Ieven
VAKB Leuven
08. 02. 2012
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• Which viruses can we detect?• What is the appropriate specimen?• Diagnosis of pediatric viral respiratory infections
- Do antigen tests still have a role in diagnosis of pediatric RTI ?- Molecular based tests- Does serology have an additional value?
• Epidemiology of pediatric viral respiratory infections- Prevalence of known and new respiratory viruses- Single versus co-infections- Role of respiratory viruses: pathogens or colonizers?
- Quantitative testing to predict severity?
Diagnosis and importance of viral respiratory tract infections in children
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• Unidentified CPE on tMK cells • Sucrose gradient: EM paramyxovirus• RNA isolation• Random Arbitrarily Primed PCR – cloning sequencing
2001: hMPV
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Human coronaviruses: common cold viruses
• (+) RNA genome
• Discovered early 60’s after inoculation of material of human common
cold on human embryonic trachea cultures
• Multiply very slowly and poorly in human kidney cultures and some
cell lines
• For years only OC43, 229E known: molecular techniques
discovered more
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2003: HCoV SARS
Novel coronavirus identified in SARS patients
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2005: HCoV NL 63
2005: HCoV HKU1
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2005: Boca virus
2007: rhinovirus C
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The main respiratory targets in molecular diagnostic tests
• Those in our routine panel:- Influenza A (IFVA)- Influenza B (IFVB)- Parainfluenza
(PIV) 1-4- Respiratory syncytial virus
(RSV)- Adenoviruses (ADV)- Metapneumovirus (hMPV)
• Those extra assays that many would consider important:
- Rhinoviruses- Enteroviruses- Coronaviruses (OC43, 229E,
NL63 and HKU1)- IFVA sub-typing- Bocavirus- Atypicals: M.pn., C. pn., Leg.
pn., Bordetella pertussis
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• Which viruses can we detect?• What is the appropriate specimen?• Diagnosis of pediatric viral respiratory infections
- Do antigen tests still have a role in diagnosis of pediatric RTI ?- Molecular based tests- Does serology have an additional value?
• Epidemiology of pediatric viral respiratory infections- Prevalence of known and new respiratory viruses- Single versus co-infections- Role of respiratory viruses: pathogens or colonizers?
- Quantitative testing to predict severity?
Diagnosis and importance of viral respiratory tract infections in children
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What is most appropriate specimen?
Nasopharyngeal aspirates or washes• Specimens of choice for viral
detection• Advantage
- Enough epithelial cells todetect respiratory viruses
• Disadvantage– Hard on the patients?– Require suction device
mucus extractor– Impractical to have in a
doctor office setting
RSV for NPA sample
Mucus Extractor
Hindiyeh M et al, 2007Meerhoff TJ et al Eur J Clin Microbiol Infect Dis 2010; 29: 365-71
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Sampling method: Flocked NPS
Pernasal Flocked Swab
The fibers have an hydrophilic action
• Soft brush for improved epithelial cells collection
• Less traumatic on the patient
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Flocked swabs or conventional rayon swabs?
Daley P. et al J Clin Microbiol. 2006; 44: 2265-7.
0
10
20
30
40
50
60
70
Conventional Swab New Swab
Nasal (N=16)
Nasopharyngeal(N=15)
Mean respiratory epithelial cell yield among
volunteers sampled by collecting NPS and NS
using flocked or rayon
Type of viral infection
Total no. of cells/hpf No. of infected cells/hpf (95% CI)
Flocked swab Rayon swab Flockes swab Rayon swab
Influenza A virus (20)
67.2 29.3 15.8 (9.7-21.9) 7.2 (3.6-10.8)
RSV (21) 51.7 19.6 32.6 (18.7-46.7) 11.0 (6.1-15.9)
DFA negative (20) 82.4 24.8 0 0
Mean of total and infected respiratory cells from NP
samples by flocked and rayon swabs
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• Nasopharyngeal flocked swabs (NFS) and nasal washing (NW) compared for detection of respiratory viruses by Mx PCR and RSV by IF
• NFS was superior to NW for detection of viruses by Mx-PCR- Sens 89.6% vs 79.2% P= 0.0043
• NFS was non inferior to NW for detection of RSV by IF
• NFS showed a 96.7% agreement with NPA or 93% sensitivity
Improved detection of respiratory viruses in children using flocked swabs
Munywoki PK et al. J Clin Microbiol 2011; 49: 3365-3367
Faden H J Clin Microbiol 2010; 48: 3742-3743
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• Which viruses can we detect?• What is the appropriate specimen?• Diagnosis of pediatric viral respiratory infections
- Do antigen tests still have a role in diagnosis of pediatric RTI ?- Molecular based tests- Does serology have an additional value?
• Epidemiology of pediatric viral respiratory infections- Prevalence of known and new respiratory viruses- Single versus co-infections- Role of respiratory viruses: pathogens or colonizers?
- Quantitative testing to predict severity?
Diagnosis and importance of viral respiratory tract infections in children
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Effect of Variables on Detection rates of the Flu A RT-PCR, Isolation, and ELISA
0
20
40
60
80
100
0 - 4 5 - 19 20 - 40 > 40
RT-PCR Virus isolation ELISA
Patient age (years)
A
0
20
40
60
80
100
0 - 2 3 - 5 > 5
RT-PCR Virus isolation ELISA
B
Onset-Testing (days)
01020304050
60708090
100
NA n=54 NPS n=65 TS n=56 SP n=41
OIA 14 Day Culture
Per
cen
t o
f P
osi
tive
sp
ecim
ens
Specimen Type
Steininger C et al. J Clin Microbiol. 2002; 40: 2051-56 Casiano-Colon et al. J Clin Virol. 2003; 28: 169
Rapid Ag tests useful in young children but in of limited value in adults !
NPA are superior to Nasal or Throat Swabs !
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Antigen-based Rapid Diagnostic Assays
• Usually less sensitive than other methods
- Median sensitivity: e.g. Zstat Flu 69%
- Directigen Flu A + B 87%, Flu OIA 72%, RSV OIA 88%
- Quick Vue Flu 79%, Testpack RSV 70%
• Sensitivity depends on specimen type
• Individual or pooled monoclonal antibodies: Flu A/B, PU 1-3, RSV, adenovirus
• Sensitivity generally higher than other rapid tests- Flu A : 40-90%- Flu A+B: 60-90%- RSV : 94%- PIV : 70-80%- Adenovirus: 22-67%
Henrickson K. Ped Infect Dis J 2004; 23:S6-10
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New Antigen-based Rapid Diagnostic Assays
• The ESPLINE Influenza A & B-N is a user friendly, rapid direct antigen assay with a very good performance: sens 93% and spec 97%
• The test is less sensitive to detect H1N1 compared to seasonal flu. • Due to its simplicity it facilitates urgent testing
• 3M A+B: superior results compared to BinaxNOW; effective 1st line triage
• BinaxNOW RSV is highly sensitive in children with bronchiolitis, but sens is low in non-bronchiolitis illness: 89% vs 38%
De Witte E et al. Eur J Clin Microbiol Infect Dis 2011: 100212R1
Ginocchio C et al. J Clin Virol 2009; 45: 146-149
Miernyk K et al. J Clin Virol 2011; 50: 240-243
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New Antigen-based Rapid Diagnostic Assays
• Addition of assays for detection of picornaviruses and hMPV increased the diagnostic yield by DFA from 35% to 58% (P < 0.0001)
• DFA, or EIA, is even in the “PCR era” a valid, rapid, flexible and cheap method for detection of respiratory viruses in a pediatric population
Sadeghi C et al. BMC Infect Dis 2011: 11: 41 Fuanzalida L et al. Clin Microbiol Infect 2010; 16: 1663
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Conventional and Real-Time Mono- and Multiplex NAAT
Author targets Species detected
Fan, J et al. 1998 2 RSVA, RSVBScheltinga et al. 2005 2 hMPN, RHIMcDonough et al. 2005 4 M. pn., C. pn., L. pn., B. pertussisGunson et al. 2005 12 IFL A and B, PFL 1,2,3 RHI, hMPN
RSVA and B, COR E229, OC 43,NL63 in 4 triplex reactions
Loens et al. 2007 3 M. pn., C. pn., L. pnChoi et al. 2006 12 in 4 multiplex and one monoreactionTiveljung et al. 2009 16 in 13 reactions: IFL A and B, RSV A+B,
PFL 1+3, PFL 2+ hCoV-229E, ADE, hMPV, RHI,ENT, HCoV-OC43, HCoV-NL63 and HKU, HBoV
Ieven M, J Clin Virol 2007; 40: 259-76
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kit targets Species detected
Xpert FluA, Cepheid 2 Influenza A and subtypingRSV,ASR, Cepheid 2 RSVA, RSVBProPneumo-1, Prodesse 2 M. pneumoniae, C. pneumoniaeRespiFinder plus, Pathofinder 18 IFL A/B, PFL 1-4, RHI, hMPN,
RSV A/B, AV, 3 coronaviruses, M. pn., C.pn., L.pn., Bordetella pertussis
SeeplexRV, Seegene 19 S. pneumoniae, H. influenzae, M. pn., C.pn.,L.pn., IFL A and B, RSV A/B, PFL 1-3, RHI, 3 coronaviruses, AV, HBoV, EV
xTAG RVP, Luminex 19 IFL A ( H1, H3, H5, non-specific ) and B, PFL 1-4, RSV A/B, ADE, hMPV, RHI/ENT,SARS-COR, HCoV OC43, HCoV 229E, HCoV NL63 and HKU1
Commercially available Mono- and Multiplex tests
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PCR based tests: limited target versus multiplex detection
Limited target detection• Usually analytical sens.• Lower cost• Often lower TAT• In outbreak situations
- Influenza, H1N1- RSV, L. pn, M.pn
• As first approach - in high prevalence periods- if therapeutic implications
• Influenza, Legionella spp, Mycoplasma pn., B. pertussis
• Outside normal lab working hrs
Multiplex detection• In >90% similar results• Expensive• TAT usually > 4-6hours• For epidemiological studies
- Prevalence of respiratory etiologies
- Role of respiratory viruses• As add-on diagnostic test
- In severely ill patients- In immunocompromised
• For virus discovery studies
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• Increase in diagnostic yield from 37% to 57%, or even > 75%- Main improvement: previously not detected viruses
Tiveljung-Lindell A et al. J Med Virol 2009; 81: 167-175Hamano- Hasegawa K et al, J Infect Chemother 2008; 14: 427-432
• in diagnostic yield from 24% to 43% or even > 66% in children, from 3.5% to 36% in adults
Van de Pol et al. J Clin Microbiol 2007;45: 2360-6 Gharabaghi F et al Clin Microbiol Infect 2011;
• Acute RTI in elderly and children: up to 40%: - mostly rhino, RSV, hMPV, and influenza
Renwick et al 2007, Regamey et al 2008 Jartti et al 2008,Caram et al 2009, Jin et al 2009
Significant increase in diagnostic yield
Impact of molecular diagnostics compared to conventional diagnostics
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Serology for the Diagnosis of Viral RTI ?
• Rarely helpful in rapid diagnosis of acute infection:
- IgG: only 4 fold rise between acute and late phase serum
specimens are informative:
- Single high IgG denotes past infection
- IgM may appear late or not at all: 10 to 50% of patients with
documented infections remain serologically negative
• Useful in epidemiologic studies
• Useful in vaccine studies
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Serodiagnosis of Human Bocavirus Infection
• Paired serum samples from children with wheezing, previously tested for 16 resp viruses
• Immunoblot assays using 2 recombinant HBoV antigens• Results:
- 24/49 (49%) of PCR + had IgM antibodies- 36/49 (73%) of PCR + had IgG antibodies- 29/49 (59%) of PCR + had IgM + in IgG antibody level:
• 91% of in IgG antibody level: high load of HBoV DNA: acute infection
Serology on acute phase sample: too insensitive
Serologic testing correlates with high viral loads and viremia
Max diagnostic accuracy, both qPCR and serological testing
Kantola K et al., Clin Infect Dis 2008; 46 540 - 46)
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Importance of PCR in the diagnosis of Mycoplasma pneumoniae infections
• PCR based detection: most sensitive: 87%• Sensitivity of serology: 58%• 7/32 patients only diagnosed by serology
• serology too insensitive for diagnosis of M. pneumoniae during early phase
• Combination of PCR and serology detects most cases
Dekeyser S et al., Pathol Biol 2011; 83-87
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• Which viruses can we detect?• What is the appropriate specimen?• Diagnosis of pediatric viral respiratory infections
- Do antigen tests still have a role in diagnosis of pediatric RTI ?- Molecular based tests- Does serology have an additional value?
• Epidemiology of pediatric viral respiratory infections- Prevalence of known and new respiratory viruses- Single versus co-infections- Role of respiratory viruses: pathogens or colonizers?
- Quantitative testing to predict severity?
Impact of molecular methods on the diagnosis of
respiratory tract infections
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Epidemiology of viral respiratory tract infections in children
• 237 patients with ARTI included from 10.2006 to 04.2007• 52.3% positive for 1 or more viruses (12%), more in hospitalized
• Picornaviruses: 43.6%• RSV: 24.3%, leading to hospitalisation in 85.3% of cases• More co-infections with hMPV: 55.6% compared to RSV: 11.8% or PIC
• PIC: most frequently involved in co-infections; not related to severity
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Hustedt J et al.Yale J Biol Med 2010; 83: 193-200Louie JK et al Pediatr Infect Dis J 2009; 28: 337-339
The changing face of pediatric respiratory tract infections
Viral RTI in children <1yr• RSV remains important cause
of LRTI
• hRV and hCoV: not only in UTRI but also in LRTI
• hMPV and hBoV joined the list if significant contributors
hMPV 10%
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- Most prevalent in (young) children ~ 10 % of children with RTI
- Immunocompromised individuals (fatal cases!)
- Elderly
- Normal individuals > 2-3 % of RTI in community surveillance studies
Osterhaus and Fouchier, The Lancet 2003v.d. Hoogen et al., JID 2003
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Van den Hoogen BG et al. Nat. Med. 2001; 7:719-724
Age (Years)
0.5 - 11 - 22 - 55 - 10
10 - 20> 20
8 - 991
n tested
20202020202072
n positive (%)
5 (25)11 (55)14 (70)20 (100)20 (100)20 (100)72 (100)
Immunofluorescence assays Virus neutralization assays
n tested
12138444
11
n positive (%)
3 (25)4 (31)3 (38)
4 (100)3 (75)3 (75)
11 (100)
Titre range
16-3216-32
16-51232-25632-12832-12816-128
1Sero-archeological analysis using sera collected in 1958
Human metapneumovirus
Seroprevalence in The Netherlands
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Clinical picture of hMPV infections
• The mean age of children infected - 11.6 mo• Up to 12% of all LRTI • Most children have a mild upper URTI • Resembling RSV, slightly milder• Preterm infants may be more susceptible.• Reports have described
- bronchiolitis 59% - pneumonia 8%- croup 18% - asthma exacerbation 14%
• Associated diseases:- conjunctivitis, otitis media- febrile seizures- diarrhoea, rash
59%18%
14%8%
McAdam AJ et al. J Infect Dis 2004; 190: 20-6
Esper F et al. J Infect Dis 2004; 189: 1388-96
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hMPV resembling RSV: Similar but Different?
• RSV: more common than hMPV in infants <6 mo. • hMPV similar to RSV, majority of hMPV cases occur in young (<5yrs) • Seasonality with RSV: hMPV later
• co-infection with RSV: More severe?
Contradictory
In 1 study, hMPV/RSV coinfection in 70%
Disease severity and hospitalization appears more common with RSV Osterhaus A, et al. Lancet. 2003; 361:890-891
Boivin G, et al. Emerg Infect Dis. 2003;9:634-640
Greensill J, et al. Emerg Infect Dis. 2003; 9: 372-375.
McAdam AJ et al. J Infect Dis 2004; 190: 20-26
Esper F et al. J Infect Dis 2004; 189: 1388-96
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Calvo C et al. Acta pediatrica 2010; 99:883-887
Epidemiology of viral respiratory tract infections in infants with bronchiolitis
In hospitalized infants, RSV is the most frequent agent in bronchiolitis
in winter, but other viruses may play a significant role wit RV, hBoV and
MPV as most significant ones;
Clinical characteristics are similar
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Garcia-Garcia ML et al. Pediatric pulmonology 2010; 45: 585-91
Emerging respiratory viruses in children with severe acute wheezing
• viruses detected in 71% of acute wheezing episodes• RSV most commonly
detected virus: 27%• Rhinovirus in 24%• Adenovirus 18%• Rate of viral detection
in infants (77%) than in older children (60%)
• RSV and rhino most prevalent in wheezing; emerging viruses hBoV and hMPV also important
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Maffey A et al. Pediatric Pulmonology 2010; 45: 619-625
Respiratory viruses and atypicals in children with asthma exacerbations
• Potential causative agent detected in 78% of patients• More in young children• RSV most commonly
detected : 40%• Rhinovirus in 25%• M.pneumoniae: 4.5%• C.pneumoniae: 2%
high prevalence of resp viruses in asthma exacerbations
RSV and rhino most prevalent; hMPV also important
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The role of rhinovirus infections in children
• Retrospective study of 580 children during 1987-2006- Median age: 1.9 years, 27% underlying medical condition- 16% of in patients treated in pediatric ICU
• Prospective study including all children > 1 month- Rhinovirus detected in 28% of 163 hospital episodes- Acute wheezing in 61% children with RV and in 31% with RSV- 50% of RV strains belonged to newly identified group C
• Group C RV accounts for a large part of RV hospitalizations• Acute wheezing: most frequent manifestation in hospital setting
• Hospitalization rates of HRV positive children with wheezing is similar to that of RSV
Peltola V et al. J Med Virology 2009, 81: 1831-1838
Pietrowska Z et al. Ped Infect Dis J 2009, 28: 25-29
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Fairchok MP et al. J Clin Virol 2010; 49: 16-20
Epidemiology of viral respiratory tract infections in children in daycare
Viral RTI in children <30 months in fulltime daycare
• At least 1 virus detected in 67% of RTI : 2x more than previously reported
• hRV most important• Co-infections common: 27%• Severity of illness not worse
Rhinovirus, RSV and adenovirus have greatest impact on young
children in daycare
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Brand HK et al. Pediatric Pulmonology 2011, 162: 88-90
Clinical relevance of infection with multiple viruses?
• children < 2yrs old with bronchiolitis:• Mild: no supportive treatment• Moderate: supplemental oxygen and/or nasogastric feeding• Severe: mechanical ventilation
• Mx PCR for 15 viruses on NPA
• Results: overall 211 viruses detected in 142 NPA• RSV most commonly detected virus: 73%• Rhinovirus in 30%• Other respiratory viruses in < 10% of samples
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39Brand HK et al. Pediatric Pulmonology 2011, 162: 88-90
Clinical relevance of infection with multiple viruses?
• RSV detected as a single virus infection in 59% of positives followed by hMPV as single infection in 56% of hMPV positives
• Other viruses less frequently detected as single virus infections• hBoV, PeV and AdV: only detected in combination with other viruses
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Importance of infection with multiple viruses?
Children < 3m Children >3m
• Children younger than 3 months: less often infected by multiple viruses compared to children older than 3 months: 25% vs 65%
• Infection with 2 or more viruses: more frequent in children with mild or moderate disease than in those with severe disease
The detection of more than one virus is not associated with increased disease
severity in children with bronchiolitis
Co- infections not associated with illness severity in acute febrile RTIBrand HK et al. Pediatric Pulmonology 2011, 162: 88-90
Suryadevara M et al. Clinical Pediatrics 2011, 50: 513-51
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De Vos N et al. Eur J Clin Microbiol Infect Dis 2009; 28: 1305-1310
The role of bocavirus infections in a belgian pediatric population
N(%)
Total mono and co-infections 272 (61%)
Co-infections 53 (19%)
AdV/RSV 18
hBoV/RSV 10
hBoV/AdV 7
AdV/hMPV 4
All other combinations <=3
• 404 patients with ARTI included during winter 2004 - 2005• 61% positive for 1 or more viruses
• bocaviruses: 11%• Adenovirus: 13%• More co-infections with AdV: 62% compared to hBoV: 49%
• Causal role for hBoV in RTI is still a topic for debate: Q-PCR?
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Individual patient care: Is viral quantification useful?
In case of PIV, rhinovirus
• Total viral load is related to clinical diagnosis in children presenting at emergency room
In case of rhinovirus
• At high viral loads (> 106 RNA copies/ml): HRVs may cause severe LRTI
• At medium-low viral loads (<105 RNA copies/ml): may represent only bystander
»
Utokaparch S et al. Pediatr Infect Dis J 2011; 30: e18-e23
Gerna G et al. J Med Virol 2009; 81:1498-1507
• At high viral loads (> 104.5 RNA cps/ml): HRVs likely to be the cause of presenting LRTI
• At medium-low viral loads (<104.5 RNA copies/ml): may represent only bystander
• Q PCR: maybe the next necessary step?
»
Jansen R et al. J Clin Microbiol 2011; 49: 2631-36
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Diagnosis and importance of viral respiratory tract infections in children
• Molecular methods have contributed significantly to an increased yield of etiologic agents detected in RTI.
• NPA or nasopharyngeal flocked swabs are the most appropriate specimens.
• There is still a role for antigen based methods especially
for detection of RSV and hMPV in children.
• Serology is of limited value in the acute phase of RTI.
• The role of hRV and hMPV become more clear in LRTI.