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 …