expanding our knowledge about paediatric pneumonia · burden of childhood pneumonia deaths • 7.6...
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Expanding our Knowledge
about Paediatric Pneumonia
David Murdoch
Department of Pathology
University of Otago, Christchurch
Outline
• The global burden of childhood pneumonia
• The challenges of determining the microbial
causes of pneumonia in children
• Changing the paradigm about the
pathogenesis and causes of pneumonia
Burden of Childhood Pneumonia
Deaths
• 7.6 million deaths
among children
<5y in 2010
• 18% (1.4 million)
were caused by
pneumonia
Global causes of mortality in children <5 yearsLiu et al. Lancet 2012; 379: 2151-61
Nearly 70% of Childhood Pneumonia
Deaths Occur in Africa & South Asia
Projections based on Williams BG et al Lancet 2002
Each dot representing 1000 deaths
52% of deaths occur in 5
countries:
– India
– Nigeria
– Democratic Republic of
Congo
– Afghanistan
– Pakistan
Global pneumonia deaths in children
<5 years old in millions (% of all deaths)
Source: Black R, Lancet 1993; Black R, Lancet 2010; Liu L, Lancet 2012.
Key Interventions for Pneumonia Control
Some Outstanding Issues in
Childhood Pneumonia
• Defining the most important causes of
pneumonia in children from developing
countries
• Improving pneumonia diagnostics
• Establishing the priorities in vaccine
development
• Identification of other preventative measures
• Improving assessment of disease severity
Why is it Important to Know the
Microbial Causes of Pneumonia?
• To better direct antibiotic treatment
• Detection of antibiotic resistance
• Identification of unexpected or unusual
causes
• Surveillance
• Informing vaccine design
A Wide Variety of Organisms can
Cause PneumoniaBacteria• Streptococcus pneumoniae
• Haemophilus influenzae
• Mycoplasma pneumoniae
• Moraxella catarrhalis
• Legionella species
• Chlamydophila pneumoniae
• Staphylococcus aureus
• Klebsiella pneumoniae
• Acinetobacter species
• Pseudomonas species
• Coxiella burnetii
• Chlamydia psittaci
• Francisella tularensis
• Yersinia pestis
• Bacillus anthracis
• Burkholderia pseudomallei
• Mycobacteria
Viruses• Influenza A and B• Respiratory syncytial virus• Adenoviruses• Parainfluenza viruses• Coronaviruses• Varicella zoster virus• Measles virus• Cytomegalovirus• Herpes simplex virus
Fungi• Pneumocystis jiroveci
• Cryptococcus neoformans
• Coccidioides immitis
• Histoplasma capsulatum
Parasites• Paragonimus westermani
This list is not complete!
Traditional View of Pneumonia
Pathogenesis1. Pathogenic microbes
colonise the upper airways
2. Aspiration of microbes into
lungs
3. Host response causes
pneumonia
Each episode of pneumonia is
caused by a single pathogen
Scott et al. J Clin Invest 2008;118:1291-1300
Causes of Severe PneumoniaHIV-negative children in developing countries
1995-2005
• 50% cases caused by two pathogens (S. pneumoniae and
H. influenzae)
Some Pneumonia Pathogens are also
Colonizers of the Upper Respiratory Tract
• For example:– Streptococcus pneumoniae, Haemophilus influenzae,
Staphylococcus aureus
• Implication:– Detection of these organisms in a respiratory
specimen is not necessarily predictive of pneumonia aetiology
• For only a few organisms is detection in respiratory specimens regarded as 100% predictive of pneumonia aetiology– e.g. Legionella spp., Mycobacterium tuberculosis
Pneumonia Pathogens can also Cause
Other Respiratory Syndromes
• Common cold, e.g. rhinoviruses, coronaviruses
• Pharyngitis, e.g. adenoviruses
• Epiglottitis, e.g. H. influenzae
• Croup, e.g. parainfluenza viruses
• Implication:
– Detection of these organisms in a respiratory
specimen may reflect concomitant or recent upper
respiratory infection
Specimen Collection
• Difficulty in obtaining specimens from the site
of infection is the fundamental problem in
pneumonia diagnostics
?
Bacterial vs Viral Pneumonia
• This is a traditional aetiological classification of pneumonia
• However, bacteria and viruses do interact in the pathogenesis of pneumonia
• Bacterial pneumonia is likely responsible for most influenza deaths
Polymicrobial Infections
• With use of new diagnostic technology,
especially multiplex PCR, multiple pathogens
are being detected more frequently in single
specimens
• Testing of multiple specimen types increases
the number of potential pathogens identified
• Most studies of pneumonia aetiology show
about 25% polymicrobial infections
The PERCH Project
Aims of PERCH
• Provide a contemporary picture of the causes
of severe pneumonia in young children from
developing countries
• Determine the risk factors for pneumonia
• Provide evidence to improve policies for
pneumonia treatment and prevention
Study Design
• Case-control study
• 7 study sites in Africa and Asia
• 2 year study period (until the beginning of 2014)
• Intensively investigate all children aged <5 years old
admitted to hospital with severe pneumonia
• Use state-of-the-art laboratory tests to determine
the causes of pneumonia
• Use statistical modelling of the data to draw
inferences about global patterns of disease
PERCH sites
* PERCH Coordinating Center
*
*
*
*
*
* Core team members
**
PERCH Laboratory TestingBody Fluid Laboratory Analyses
Blood Culture, serology,* PCR for pneumococcus
Nasopharyngeal swab* Bacterial culture for pneumococcus (and serotyping)
Combined throat and
nasopharyngeal swabs*
Multiplex PCR
Induced Sputum Microscopy and culture (including for mycobacteria)
Multiplex PCR
Lung Aspirate
(at select sites)
Microscopy and culture (including for mycobacteria)
Multiplex PCR
Pleural Fluid Microscopy and culture (including for mycobacteria)
Multiplex PCR
Post-mortem lung tissue
(at select sites)
Histology
Microscopy and culture (including for mycobacteria)
Multiplex PCR
Gastric Aspirate Mycobacterial culture
Urine* Antibiotic activity testing
*specimens tested from controls as well
PERCH Multiplex Real-time PCR
Target PathogensRNA targets DNA targets
Influenza A Adenoviruses
Influenza B Bocavirus
Influenza C Cytomegalovirus
Respiratory Syncytial virus A and B Streptococcus pneumoniae
Parainfluenza viruses 1-4 Haemophilus influenzae type b
Rhinoviruses H. influenzae non-typeable
Enteroviruses Staphylococcus aureus
Coronaviruses OC43, 229E, NL63, HKU1 Mycoplasma pneumoniae
Human metapneumovirus Legionella species
Parechovirus Chlamydophila pneumoniae
Moraxella catarrhalis
Klebsiella species
Salmonella species
Bordetella pertussis
Pneumocystis jiroveci
What are the Expected Analytic Outcomes
from PERCH?
• To establish proportions of
childhood pneumonia episodes
attributable to various pathogens
to inform population prevention
and treatment strategies
• To identify attributable
pathogens on an individual basis
to inform treatment algorithms 0
10
20
30
40
Pro
ba
bil
ity
(%
)
A B C D E F G H I J K L M N O P Q R
Pathogen
Pathogen Pie – Blood culture, IS, NP/OP,
adjusted for case/control
Bacteria alone
16%
Virus alone
22%
Time for a Paradigm Shift?
• New paradigm:
– Pneumonia is (usually) a polymicrobial disease
– Pneumonia is the host response to mixed upper
respiratory flora getting in the wrong place
– If the mixed flora includes a particularly virulent
pathogen, that microbe may predominate
– Occasionally, specific highly-virulent pathogens
may cause pneumonia by themselves (e.g.
Legionella)
Pneumonia Pathogenesis
The New Paradigm1. Normal flora colonise the
upper airways
2. Coincident viral upper
respiratory infection
3. Aspiration of upper
respiratory flora into lungs
4. Host response causes
pneumonia
5. Presence of a virulent
pathogen may result in
more severe disease,
bacteraemia, etc
Implications of the Paradigm Shift
• It explains why:
– There are big gaps in the aetiology pie chart
– Good quality sputum frequently contains
“oropharyngeal flora” only
– Two or more potential pneumonia pathogens are
frequently detected in individual patients
Implications of the Paradigm Shift
• Does not lessen the importance of individual
pathogens
• Does not lessen the importance of prevention
by vaccination
• Redirects research efforts to focus on:
– the upper respiratory microbiome
– triggers for pneumonia
– bacterial-viral interactions
What are the Roles of Viruses in
Pneumonia?
• Primary viral pneumonia does exist
– Possibly less common than once thought
– Particularly associated with specific viruses (e.g.
SARS coronavirus, influenza H5N1)
• Viruses play a prominent role in bacterial
pneumonia
– Viral URTI may be a key precipitant in most cases
of bacterial pneumonia
Keep watching this space …Keep watching this space …