Nigel Bruce - PowerPoint Presentation

Slide1
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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 worldSlide3

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 trialMechanistic studiesConclusionsNew/ongoing field trialsSlide4

Household air pollution

3 billion use solid fuel as primary cooking fuel

1.2 billion no electricity: use simple

kerosene lamps

I

nefficient stoves/lamps lead to high emissions of

‘PIC’

Health-damaging pollutants:

Small particulates (PM2.5)

Toxic gases, carcinogens and irritants

Typical PM

2.5

levels 500 µg/m

3, vs. WHO AQGs of 10Exposure highest for women (pregnant) & young childrenSlide5

Solid fuel use for cooking: 2010Slide6

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 cultureMechanistic studies:

In vivo: survival after infection with S. Pneumoniae (mice) In vitro: C-loaded AM killing of S. pneumonia

e. Slide7

Death rates from ALRI in children under 5 years (2010)

Source WHO

Ecological associationSlide8

Death rates from ALRI in children under 5 years (2010)

Source WHO

Percentage of homes relying on solid fuels for cooking (2010)

Source WHO

Ecological associationSlide9

Systematic review of epidemiological studies

Published

(

Dherani

et al 2008)

UpdatedEligible studies:Cross-sectional, analytic observational, RCT

Exposure: very few measured HAP or exposure  fuel, stove-type, behaviour contrastOutcome: reported symptoms/signs

 community ALRI  clinical diagnosis  CXR and bacteriologyResults:All non-fatal ALRI (severity not defined); n=21

Non-fatal, severe ALRI; n=4Fatal ALRI; n=4Slide10

SRMA: pooled ORs (95% CI)

Outcome

N

I

2

(p-value)

Random or Fixed effect

Publication bias

(p-value)

OR

(95% CI)

P-value

All ALRI*

(severity not defined)21

61% (p<0.0001)RandomBegg’s

: 0.56

Egger’s: 0.09

1.56

(1.33, 1.83)

P<0.0001*Includes O’Dempsey (Gambia 1996): Pneumococcal disease on blood culture (79% pneumonia) OR=2.55 (0.98 – 6.65) Slide11

SRMA: pooled ORs (95% CI)

Outcome

N

I

2

(p-value)

Random or Fixed effect

Publication bias

(p-value)

OR

(95% CI)

P-value

All ALRI*

(severity not defined)21

61% (p<0.0001)RandomBegg’s

: 0.56

Egger’s: 0.09

1.56

(1.33, 1.83)

P<0.0001Severe1451% (p=0.10)RandomN/A2.04(1.33, 3.14)P=0.001Fatal240% (p=0.64)FixedN/A2.80(1.81, 4,34)P<0.00011Severe: 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) Slide12

RESPIRE Trial

Objective: impact of HAP reduction on pneumonia incidence in children

<

18 months

Primary: ITT analysis

Secondary: exposure-response analysisRural, highland communities of Comitancillo

and San Lorenzo, alt. 2200 – 3000 m518 homes (pregnant woman, child <4 months) randomised to keep open fire or use ‘plancha’

Children followed to 18 months: ~30,000 child weeksSurveillance for pneumonia cases and all deaths Slide13

Control and intervention stoves

Traditional open 3-stone fire: kitchen 48-hour PM

2.5

levels of 500 - 1000

μ

g/m

3

The

plancha

chimney wood stove, locally made and popular with households Slide14

Overview of child health outcomes assessment

Home

Community centre

Hospital

Child dies

Child dies

Verbal

autopsy

Verbal autopsy

Health outcome

definitions

Weekly visit

Well

Mild illness

Referral to study doctor

Assessed by duty doctor

Study team obtain CXR and inpatient data and diagnosis

Follow-up at weekly visit

Study doctor examines

Pulse oximetry

If pneumonia, RSV* test and refer for CXR

Refer if very ill

*

Respiratory syncytial virusSlide15

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 PMMother breath CO (COHb)Slide16

Effect of intervention stove on (

i

) kitchen IAP and (ii) personal exposure

↓90%

↓52%

↓61%

Smith et al, J Exp Sci Env Epidemiol 2009Slide17

Physician-assessed outcomes (ITT)

Case finding

Outcome

RR (95% CI)

P-value

Physician diagnosed pneumonia

Investigations

:

- Pulse

oximetry

- RSV direct antigen test

- Chest X-ray

All

0.78 (0.59, 1.06)

0.095

- Severe (hypoxic)

0.67 (0.45, 0.98)

0.042

CXR +

ve

0.74 (0.42, 1.15)

0.231

- CXR +

ve

& hypoxic

0.68 (0.36, 1.33)

0.234

RSV +

ve

0.76 (0.42, 1.16)

0.275

- RSV +

ve

& hypoxic

0.87 (0.46, 1.51)

0.633

RSV -

ve

0.79 (0.53, 1.07)

0.192

- RSV –

ve

& hypoxic

0.54 (0.31, 0.91)

0.026Slide18

Exposure-response analysis

Mean PM2.5 exposure equivalent (µg/m

3

):

OF: 250

Plancha:125

Lowest exposure decile ~50 µg/m3

Statistically significant E-R relationshipsImplications: low exposure (<30-50 µg/m3

) needed to prevent most cases

Open fire

PlanchaSlide19

Mechanisms: focus on HAP

Pollutants

Carbonaceous PM (<10 microns; <5 into alveoli)

Gases (irritant, toxic):

NO

2

, COHydrocarbons (cancer): BenzenePolyaromatic

HC (cancer): benzo [A] pyreneAldehydes (irritant):

FormaldehydeAcroleinSlide20

Mechanisms: focus on HAP

Pollutants

Carbonaceous PM (<10 microns; <5 into alveoli)

Gases (irritant, toxic):

NO

2

, COHydrocarbons (cancer): BenzenePolyaromatic

HC (cancer): benzo [A] pyreneAldehydes (irritant):

FormaldehydeAcroleinDefence mechanisms

Filtering

Immune response including:

alveolar macrophages (AM), opsonisation,

IgA

,

IgG, surfactant, plasma, etc.

Physical barrier of epithelium

Muco-ciliary

clearanceSlide21

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 2009Slide22

Impaired AM

phagocytic

function

Human AM*:

UF-CB; DEP

4 tests (silica, micro-organisms)

All ↓phagocytosisRat AM** (see graph):

Carbon-loaded AMreduced Strep pneumoniae killingMice AM***:

CAP particlesS. pneumoniaeIncreased adherence, but reduced killingIron chelation reversed

*

Lundborg

et al 2006

**

Lundborg et al 2007 (graph)***Zhou et al 2007Slide23

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 2005Slide24

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 effectConclude that redox

active metals in PM are important

Mudway et al 2005Slide25

In vivo survival following infection

Hatch (1985):

Poorer survival with PM

For CB and AAP derived PM

Tellabati

(2010)Increased survival with PM (p<0.001)

Used UF-CB

Studies of mice infected with S

. PneumoniaeTellabati et al 2010Slide26

Summary: evidence for causality

Bradford Hill viewpoints

#

Viewpoint

Summary of

evidence

1

Strength of association

OR>2 for severe/fatal

pneumonia

2

Consistency across populations/study designs

Majority of studies find report increased risk w

ith exposure (not all significant)

3

Specificity

N/A

4

Temporality (exposure precedes outcome)

Exposure has preceded infection in all studies; longitudinal studies available

5Biological gradientStatistically significant gradients in two studies6Biological plausibilityStudies show range of mechanisms are affected (Ciliatoxic; ↓AM function; ↑oxidative stress, &c)7Coherence with natural history, animal studiesHAP exposure consistent with mortality;Some animal evidence available 8

Experiment

RESPIRE; adult cohort study from China

9

Analogy

Other main sources (AAP,

smoking)

increase riskSlide27

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 pneumoniaEvidence for severe, fatal, non-RSV, pneumococcal disease

Mechanistic studies show plausible pathways and effectsWhat 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 effectSlide28

New and ongoing RCTs:

Birth outcomes and ALRI

Country

Investigator group

Intervention

Investigations

Status

Malawi

Liverpool

;

Wellcome

Trust R/Centre

Fan stove

Severity Aetiology Exposure

Mechanisms

Preparation phas

e

Nepal

Johns Hopkins

Rocket

stoveLPG Severity AetiologyOngoingGhanaColumbia University; Kintampo R/CentreFan stoveLPG Severity Aetiology Exposure MechanismsRecruitingIndiaUC Berkeley; INCLENTBC: Fan stove and/or LPG TBCPilot studiesSlide29

Thank you!Slide30

Trends in SFU: 1980 - 2010Slide31

Exposure distributions in

plancha

and open fire groupsSlide32

Impact of 50% increase in exposure

The average exposure reduction for the intervention group was 50%

Pneumonia classification

Cases/child weeks

OR (95% CI; p-value) with doubling of

exposure

A: Unadjusted

B: Adjusted for confounders

C: As for B plus stove type

All

263/

30270

1.22

1.05,

1.41)

P=0.011

1.25

(1.06, 1.48)

P=0.010

1.28

(1.05, 1.56)P=0.015Hypoxaemic136/303171.35(1.12, 1.61)P=0.0011.38(1.12, 1.69)P=0.0021.39(1.07, 1.81)P=0.014Radiological85/303171.45(1.11, 1.90)P=0.0061.45(1.09, 1.93)P=0.0111.66(1.15, 2.40)P=0.007Hypoxaemic and radiological53/303231.71(1.25, 2.32)P=0.0011.71(1.20, 2.44)P=0.0032.09(1.29, 3.38)P=0.003Slide33

In vivo survival following infection

Hatch (1985):

Poorer survival with PM

For CB and AAP derived PM

Tellabati

(2010)Increased survival with PM (p<0.001)

Used UF-CB

Studies of mice infected with S

. PneumoniaeRSV 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+RSVTellabati et al 2010Slide34

Integrated exposure-response function: child ALRI incidence

AAP

SHS

Household Air Pollution

All ALRI: mixed viral and bacterialSlide35

Integrated exposure-response function: child ALRI incidence

AAP

SHS

Household Air Pollution

Average LMIC exposure

Average

RESPIREplancha

Estimate for

SRMA

All ALRI: mixed viral and bacterialSlide36

Integrated exposure-response function: child ALRI incidence

AAP

SHS

Household Air Pollution

Average LMIC exposure

Average

RESPIREplancha

Estimate for

SRMA

2.8

2.2

1.7

0.78

0.60