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Expanding our Knowledge about Paediatric Pneumonia · PDF file Burden of Childhood Pneumonia Deaths • 7.6 million deaths among children

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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


    • 7.6 million deaths

    among children

  • 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


    – India

    – Nigeria

    – Democratic Republic of Congo

    – Afghanistan

    – Pakistan

  • Global pneumonia deaths in children

  • Key Interventions for Pneumonia Control

  • Some Outstanding Issues in

    Childhood Pneumonia

    • Defining the most important causes of

    pneumonia in children from developing


    • Improving pneumonia diagnostics

    • Establishing the priorities in vaccine


    • 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 Pneumonia Bacteria • 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

    Pathogenesis 1. Pathogenic microbes

    colonise the upper airways

    2. Aspiration of microbes into


    3. Host response causes


    Each episode of pneumonia is

    caused by a single pathogen

  • Scott et al. J Clin Invest 2008;118:1291-1300

    Causes of Severe Pneumonia HIV-negative children in developing countries


    • 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


    • 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

  • PERCH sites

    * PERCH Coordinating Center






    * Core team members

    * *

  • PERCH Laboratory Testing Body 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)


    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 Pathogens RNA 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




    P ro

    b a

    b il

    it y

    ( %


    A B C D E F G H I J K L M N O P Q R


  • Pathogen Pie – Blood culture, IS, NP/OP,

    adjusted for case/control

    Bacteria alone


    Virus alone


  • 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.


  • Pneumonia Pathogenesis

    The New Paradigm 1. Normal flora colonise the

    upper airways

    2. Coincident viral upper

    respiratory infection

    3. Aspiration of upper

    respiratory flora into lungs

    4. Host response causes


    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

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