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Nigel Bruce Department of Public Health and Policy, University of Liverpool, UK

Indoor air pollution and vulnerability to bacterial pneumonia in young children. Lessons from the developing world. Nigel Bruce Department of Public Health and Policy, University of Liverpool, UK. Overview. Indoor (household) air pollution

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Nigel Bruce Department of Public Health and Policy, University of Liverpool, UK

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  1. Indoor air pollution and vulnerability to bacterial pneumonia in young children Lessons from the developing world Nigel Bruce Department of Public Health and Policy, University of Liverpool, UK

  2. Overview • Indoor (household) air pollution • Available ‘measures’ of possible bacterial pneumonia in young children • Three types of evidence • Ecological • Epidemiological studies: • Systematic review/meta-analysis • RESPIRE trial • Mechanistic studies • Conclusions • New/ongoing field trials

  3. 3 billion use solid fuel as primary cooking fuel 1.2 billion no electricity: use simple kerosene lamps Inefficient stoves/lamps lead to high emissions of ‘PIC’ Health-damaging pollutants: Small particulates (PM2.5) Toxic gases, carcinogens and irritants Typical PM2.5 levels 500 µg/m3, vs. WHO AQGs of 10 Exposure highest for women (pregnant) & young children Household air pollution

  4. Solid fuel use for cooking: 2010

  5. Available measures of (possible) bacterial pneumonia in various types of study • Mortality (bacterial higher CF): • ALRI (mix): WHO stats; DHS • Pneumonia: diagnosed; VA? • Severe pneumonia (bacterial more likely to be severe): • Clinical signs • Hypoxaemia (pulse oximetry) • Aetiology: • Antigen tests (NPA, urine, blood, lung) • Lung aspirate or blood culture • Mechanistic studies: • In vivo: survival after infection with S. Pneumoniae (mice) • In vitro: C-loaded AM killing of S. pneumoniae.

  6. Ecological association Death rates from ALRI in children under 5 years (2010) Source WHO

  7. Ecological association Death rates from ALRI in children under 5 years (2010) Source WHO Percentage of homes relying on solid fuels for cooking (2010) Source WHO

  8. Systematic review of epidemiological studies • Published (Dherani et al 2008) • Updated • Eligible studies: • Cross-sectional, analytic observational, RCT • Exposure: very few measured HAP or exposure  fuel, stove-type, behaviour contrast • Outcome: reported symptoms/signs  community ALRI  clinical diagnosis  CXR and bacteriology • Results: • All non-fatal ALRI (severity not defined); n=21 • Non-fatal, severe ALRI; n=4 • Fatal ALRI; n=4

  9. SRMA: pooled ORs (95% CI) *Includes O’Dempsey (Gambia 1996): Pneumococcal disease on blood culture (79% pneumonia) OR=2.55 (0.98 – 6.65)

  10. SRMA: pooled ORs (95% CI) 1Severe: includes physician clinical definition (n=3) and low oxygen saturation on pulse oximetry (n=1) 2Fatal: includes verbal autopsy (n=2), parental recall of signs (n=1) and deaths in hospital following radiological confirmation of pneumonia (n=1) *Includes O’Dempsey (Gambia 1996): Pneumococcal disease on blood culture (79% pneumonia) OR=2.55 (0.98 – 6.65)

  11. RESPIRE Trial • Objective: impact of HAP reduction on pneumonia incidence in children <18 months • Primary: ITT analysis • Secondary: exposure-response analysis • Rural, highland communities of Comitancillo and San Lorenzo, alt. 2200 – 3000 m • 518 homes (pregnant woman, child <4 months) randomised to keep open fire or use ‘plancha’ • Children followed to 18 months: ~30,000 child weeks • Surveillance for pneumonia cases and all deaths

  12. Control and intervention stoves The plancha chimney wood stove, locally made and popular with households Traditional open 3-stone fire: kitchen 48-hour PM2.5 levels of 500 - 1000 μg/m3

  13. Overview of child health outcomes assessment Follow-up at weekly visit • Weekly visit • Well • Mild illness • Referral to study doctor • Study doctor examines • Pulse oximetry • If pneumonia, RSV* test and refer for CXR • Refer if very ill Assessed by duty doctor Study team obtain CXR and inpatient data and diagnosis Child dies Child dies Health outcome definitions Verbalautopsy Verbal autopsy * Respiratory syncytial virus Community centre Home Hospital

  14. Home IAP and exposure assessment methods • All homes: • 48 hr CO tube child (3 monthly) • mother (6 monthly) • Random sub-sample (n=40+40): • 3-monthly • CO (tube, Hobo) • PM (filter, pump) • Continuous PM • Mother breath CO (COHb)

  15. Effect of intervention stove on (i) kitchen IAP and (ii) personal exposure ↓90% ↓61% ↓52% Smith et al, J Exp Sci Env Epidemiol 2009

  16. Physician-assessed outcomes (ITT)

  17. Exposure-response analysis Plancha Open fire • Mean PM2.5 exposure equivalent (µg/m3): • OF: 250 • Plancha:125 • Lowest exposure decile ~50 µg/m3 • Statistically significant E-R relationships • Implications: low exposure (<30-50 µg/m3) needed to prevent most cases

  18. Mechanisms: focus on HAP Pollutants • Carbonaceous PM (<10 microns; <5 into alveoli) • Gases (irritant, toxic): • NO2, CO • Hydrocarbons (cancer): • Benzene • Polyaromatic HC (cancer): • benzo [A] pyrene • Aldehydes (irritant): • Formaldehyde • Acrolein

  19. Mechanisms: focus on HAP Pollutants Defence mechanisms • Carbonaceous PM (<10 microns; <5 into alveoli) • Gases (irritant, toxic): • NO2, CO • Hydrocarbons (cancer): • Benzene • Polyaromatic HC (cancer): • benzo [A] pyrene • Aldehydes (irritant): • Formaldehyde • Acrolein Filtering Muco-ciliary clearance Physical barrier of epithelium Immune response including: alveolar macrophages (AM), opsonisation, IgA, IgG, surfactant, plasma, etc.

  20. AM function: carbon loading • Biomass fuel users show higher carbon loading in AMs • Human (BAL) study (Malawi)* • Wood fuel users higher AM (p<0.01) • Also for kerosene lighting (P<0.001) *Fullerton et al 2009

  21. Impaired AM phagocytic function • Human AM*: • UF-CB; DEP • 4 tests (silica, micro-organisms) • All ↓phagocytosis • Rat AM** (see graph): • Carbon-loaded AM • reduced Strep pneumoniaekilling • Mice AM***: • CAP particles • S. pneumoniae • Increased adherence, but reduced killing • Iron chelation reversed *Lundborg et al 2006 **Lundborg et al 2007 (graph) ***Zhou et al 2007

  22. Oxidative stress • Human respiratory tract lining fluid model • PM obtained from dung fuel (DC PM-sample 1) • Antioxidant (Ascorbate) depleted by PM Mudway et al 2005

  23. Oxidative stress • Human respiratory tract lining fluid model • PM obtained from dung fuel (DC PM-sample 1) • Antioxidant (Ascorbate) depleted by PM • Metal chelating agent (DPTA) inhibits effect • Conclude that redox active metals in PM are important Mudway et al 2005

  24. In vivo survival following infection Studies of mice infected with S. Pneumoniae • Hatch (1985): • Poorer survival with PM • For CB and AAP derived PM • Tellabati (2010) • Increased survival with PM (p<0.001) • Used UF-CB Tellabati et al 2010

  25. Summary: evidence for causalityBradford Hill viewpoints

  26. Conclusions and next steps • 2.8 billion people exposed to high levels of HAP; >1 billion children through pregnancy and post-natally • Does this cause bacterial pneumonia? • Good evidence for ‘ALRI’ • Most ALRI in developing countries is bacterial pneumonia • Evidence for severe, fatal, non-RSV, pneumococcal disease • Mechanistic studies show plausible pathways and effects • What is needed to confirm? • New RCTs (... Ghana, Nepal, Malawi, India) • Include: exposure assessment, aetiology and severity • Further mechanistic studies (in vitro and in vivo) • Vaccine world? • Reducing HAP may reduce risk via LBW, PTB, and in first few months of life before vaccine has full effect

  27. New and ongoing RCTs:Birth outcomes and ALRI

  28. Thank you!

  29. Trends in SFU: 1980 - 2010

  30. Exposure distributions in plancha and open fire groups

  31. Impact of 50% increase in exposure The average exposure reduction for the intervention group was 50%

  32. In vivo survival following infection Studies of mice infected with S. Pneumoniae • Hatch (1985): • Poorer survival with PM • For CB and AAP derived PM • Tellabati (2010) • Increased survival with PM (p<0.001) • Used UF-CB Tellabati et al 2010 • RSV infection (Lambert 2003): • Mice treated with CB, then infected with RSV • No increased replication of RSV • Later increase in neutrophils and TNF • 2o bacterial infection only seen for CB+RSV

  33. Integrated exposure-response function: child ALRI incidence Household Air Pollution SHS AAP All ALRI: mixed viral and bacterial

  34. Integrated exposure-response function: child ALRI incidence Household Air Pollution SHS AAP Average RESPIREplancha Average LMIC exposure Estimate for SRMA All ALRI: mixed viral and bacterial

  35. Integrated exposure-response function: child ALRI incidence Household Air Pollution SHS AAP Average RESPIREplancha Average LMIC exposure 0.78 0.60 2.8 Estimate for SRMA 2.2 1.7

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