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

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

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

Household air pollution

• 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

Solid fuel use for cooking: 2010

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.

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

Source WHO

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

Ecological association

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

SRMA: pooled ORs (95% CI)Outcome N I2 (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)Random

Begg’s: 0.56Egger’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)

SRMA: pooled ORs (95% CI)Outcome N I2 (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)Random

Begg’s: 0.56Egger’s: 0.09

1.56 (1.33, 1.83)

P<0.0001

Severe1 4 51% (p=0.10)Random

N/A 2.04(1.33, 3.14)

P=0.001

Fatal2 4 0% (p=0.64)Fixed

N/A 2.80(1.81, 4,34)

P<0.0001

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)

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

Control and intervention stoves

Traditional open 3-stone fire: kitchen 48-hour PM2.5 levels of

500 - 1000 μg/m3

The plancha chimney wood stove, locally made and popular with

households

Overview of child health outcomes assessment

HomeCommunity

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 virus

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)

Effect of intervention stove on (i) kitchen IAP and (ii) personal exposure

0

1

2

3

4

5

6

7

8

Kitchen Child Mother

Ge

om

etr

ic m

ea

n C

O (

pp

m)

Open fire Plancha

↓90%

↓52%

↓61%

Smith et al, J Exp Sci Env Epidemiol 2009

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) 0.026

Exposure-response analysis

• 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

Open firePlancha

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

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

Defence mechanisms

Filtering

Immune response including: alveolar macrophages (AM), opsonisation, IgA, IgG, surfactant, plasma, etc.

Physical barrier of epithelium

Muco-ciliary clearance

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

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 pneumoniae

killing• 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

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

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

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. Pneumoniae

Tellabati et al 2010

Summary: evidence for causalityBradford Hill viewpoints

# Viewpoint Summary of evidence1 Strength of association OR>2 for severe/fatal pneumonia2 Consistency across

populations/study designsMajority of studies find report increased risk with exposure (not all significant)

3 Specificity N/A4 Temporality (exposure

precedes outcome)Exposure has preceded infection in all studies; longitudinal studies available

5 Biological gradient Statistically significant gradients in two studies6 Biological plausibility Studies show range of mechanisms are affected

(Ciliatoxic; ↓AM function; ↑oxidative stress, &c)7 Coherence 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 risk

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

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 phase

Nepal Johns Hopkins Rocket stoveLPG

• Severity• Aetiology

Ongoing

Ghana Columbia University; Kintampo R/Centre

Fan stoveLPG

• Severity• Aetiology• Exposure• Mechanisms

Recruiting

India UC Berkeley; INCLEN

TBC: Fan stove and/or LPG

• TBC Pilot studies

Thank you!

Trends in SFU: 1980 - 2010

-2 -1 0 1 2 3

0.0

0.5

1.0

1.5

2.0

Child Mean CO (ln(ppm))

Open fireVariance=0.36

Plancha stoveVariance=0.31

(b)

Pro

babi

lity

Den

sity

-2 -1 0 1 2 3

0.0

0.5

1.0

1.5

2.0

Child Mean CO (ln(ppm))

Open fireVariance=0.36

Plancha stoveVariance=0.31

(b)

Pro

babi

lity

Den

sity

Exposure distributions in plancha and open fire groups

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=0.015

Hypoxaemic 136/30317

1.35(1.12, 1.61)P=0.001

1.38(1.12, 1.69)P=0.002

1.39(1.07, 1.81)P=0.014

Radiological 85/30317

1.45(1.11, 1.90)P=0.006

1.45(1.09, 1.93)P=0.011

1.66(1.15, 2.40)P=0.007

Hypoxaemic and radiological

53/30323

1.71(1.25, 2.32)P=0.001

1.71(1.20, 2.44)P=0.003

2.09(1.29, 3.38)P=0.003

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. Pneumoniae

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

Tellabati et al 2010

Integrated exposure-response function: child ALRI incidence

AAP

SHS

Household Air Pollution

All ALRI: mixed viral and bacterial

Integrated exposure-response function: child ALRI incidence

AAP

SHS

Household Air Pollution

Average LMIC

exposure

Average RESPIREplancha

Estimate for

SRMAAll ALRI: mixed viral and bacterial

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

0.780.60