Expanding our Knowledge about Paediatric Pneumonia. David Murdoch Department of Pathology University of Otago, Christchurch

Transcription

1 Expanding our Knowledge about Paediatric Pneumonia David Murdoch Department of Pathology University of Otago, Christchurch

2 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

3 Burden of Childhood Pneumonia 7.6 million deaths among children <5y in % (1.4 million) were caused by pneumonia Deaths Liu et al. Lancet 2012; 379: Global causes of mortality in children <5 years

4 Nearly 70% of Childhood Pneumonia Deaths Occur in Africa & South Asia 52% of deaths occur in 5 countries: India Nigeria Democratic Republic of Congo Afghanistan Pakistan Projections based on Williams BG et al Lancet 2002 Each dot representing 1000 deaths

5 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.

6 Key Interventions for Pneumonia Control

7 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

8 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

9 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!

10 Traditional View of Pneumonia 1. Pathogenic microbes colonise the upper airways 2. Aspiration of microbes into lungs 3. Host response causes pneumonia Pathogenesis Each episode of pneumonia is caused by a single pathogen

11 Causes of Severe Pneumonia HIV-negative children in developing countries % cases caused by two pathogens (S. pneumoniae and H. influenzae) Scott et al. J Clin Invest 2008;118:

12 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

13 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

14 Specimen Collection Difficulty in obtaining specimens from the site of infection is thefundamental problem in pneumonia diagnostics?

15 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

16 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

17 The PERCH Project

18 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

19 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

20 PERCH sites * * * * * * * * PERCH Coordinating Center * Core team members

21 PERCH Laboratory Testing Body Fluid Blood Nasopharyngeal swab* Combined throat and nasopharyngeal swabs* Induced Sputum Lung Aspirate (at select sites) Pleural Fluid Post-mortem lung tissue (at select sites) Gastric Aspirate Urine* Laboratory Analyses Culture, serology,* PCR for pneumococcus Bacterial culture for pneumococcus (and serotyping) Multiplex PCR Microscopy and culture (including for mycobacteria) Multiplex PCR Microscopy and culture (including for mycobacteria) Multiplex PCR Microscopy and culture (including for mycobacteria) Multiplex PCR Histology Microscopy and culture (including for mycobacteria) Multiplex PCR Mycobacterial culture Antibiotic activity testing *specimens tested from controls as well

22 PERCH Multiplex Real-time PCR Target Pathogens RNA targets Influenza A Influenza B Influenza C Respiratory Syncytial virus A and B Parainfluenza viruses 1-4 Rhinoviruses Enteroviruses Coronaviruses OC43, 229E, NL63, HKU1 Human metapneumovirus Parechovirus DNA targets Adenoviruses Bocavirus Cytomegalovirus Streptococcus pneumoniae Haemophilus influenzae type b H. influenzae non-typeable Staphylococcus aureus Mycoplasma pneumoniae Legionella species Chlamydophila pneumoniae Moraxella catarrhalis Klebsiella species Salmonella species Bordetella pertussis Pneumocystis jiroveci

23 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 40 To identify attributable pathogens on an individual basis 10 to inform treatment algorithms 0 Probability (%) A B C D E F G H I J K L M N O P Q R Pathogen

24 Pathogen Pie Blood culture, IS, NP/OP, adjusted for case/control Bacteria alone 16% Virus alone 22%

25 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)

26 Pneumonia Pathogenesis 1. Normal flora colonise the upper airways 2. Coincident viral upper respiratory infection The New Paradigm 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

27 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

28 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

29 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

30 Keep watching this space