asthma: the role of the environment · 2016-12-05 · protective effect of infant infections •...

ASTHMA:

THE ROLE OF THE ENVIRONMENT

Jeroen Douwes, PhD

Massey University

Wellington, New Zealand

ASTHMA PREVALENCE – A GLOBAL PICTURE

NZ RESPIRATORY CONFERENCE 1016

<5%

5 to <10%

10 to <20%

20%

THE PREVALENCE OF ALLERGIES AND ASTHMA HAVE INCREASED

CONSIDERABLY IN THE PAST FEW DECADES


Haahtela et al., 2013

ASTHMA AND THE ENVIRONMENT: EARLY LIFE

FACTORS


- Aero-allergens

- Microbial exposure: protective, risk factor or both?

- Raw milk: protective?

- Effect modification of co-exposures?

- Have we made any progress?

PIAMA BIRTH COHORT INTERVENTION STUDY GEHRING ET AL., ALLERGY 2012;67:248-256


- Mite impermeable mattress cover (n=416), placebo (n=394), no

intervention (n=472); HDM levels at age 3 months and 8 years

HD

M

Interven

tion

PAULA BIRTH COHORT STUDY ILLI ET AL., ANN ALLERGY ASTHMA IMMUNOL 2014;112:132-139


- HDM levels at 3 months and symptoms at age 5.



- Endotoxin levels at 3 months and symptoms at age 5.



- HDM and endotoxin levels at 3 months and symptoms at age 5.

FACTORS THAT MAY “PROGRAMME” THE INITIAL SUSCEPTIBILITY

TO ASTHMA: THE HYGIENE/MICROBIOTA HYPOTHESIS

• Western populations may

have lost the previous

protective effect of infant

infections

• Decreased family size

increases risk of atopy

and asthma

• Some evidence that

infections in infancy

reduce the risk of asthma

and atopy

• Some evidence that non-

infectious agents may

also be protectiv


REDUCED MICROBIAL BIODIVERSITY: OLDER

SIBLINGS


Strachan., 1989 Birth cohort: 17,414 subjects

ENDOTOXIN EXPOSURE AT 12 MONTHS AND DOCTOR’S

DIAGNOSED ASTHMA AT 48 MONTHS (DOUWES ET AL., 2006)


ENDOTOXIN AND CHILDHOOD WHEEZE AND ASTHMA: A META ANALYSIS

MENDY ET AL., 2011


EFFECT OF ENDOTOXIN AND ALLERGENS ON NEONATAL

LUNG FUNCTION (ABBING-KARAHAGOPIAN ET AL., 2012)


• Lung function before age

2 months, N=298

• Mattress mite allergens

and endotoxin

• No associations between

allergen exposure and

lung function and

symptoms

• Mattress dust endotoxin

was associated with a

significant increase in

neonatal respiratory

compliance

Farming and asthma. Genuneit J. Pediatr Allergy Immunol 2012: 23: 509–518.


INDEPENDENT AND JOINT EFFECTS OF CURRENT AND PRENATAL ANIMAL EXPOSURE

IN NZ FARMERS’ AND RURAL REFERENCE CHILDREN - DOUWES ET AL., 2008


OR

Eczema everHay fever everAsthma everAsthma drugs in

last 12 months

Wheeze in last 12

months

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60


364;8:2011

REDUCED GUT MICROBIAL BIODIVERSITY AND NCDS


• Gut microbial diversity is inversely

associated with:

• Obesity and metabolic diseases;

• Autism, depression, anxiety, stress

• Inflammatory diseases:

• Gastrointestinal disease such as

inflammatory bowel disease and

colon cancer

• Autoimmune disease (e.g.

rheumatoid arthritis)

• Allergies and asthma

• Gut microbial diversity is positively

associated with exercise

Turnbaugh et al, 2009

Clark et al., 2014

GUT MICROBIOME AND ASTHMA: BISGAARD ET AL., 2011


- Evidence for allergies/atopy most consistent - Evidence for asthma is mixed

DO FARMERS HAVE AN ALTERED MICROBIOME? A STUDY

IN THE OLD ORDER AMISH (ZUPANICIC ET A., 2012)

RESPIRATORY CONFERENCE 1016

• Gut microbiota sequencing in 310 Amish;

• In men, the occupation of farming (n=44) was over-represented

among those with the Prevotella-dominated network (71.4%)

compared to either the Bacteroides-dominated (21.4%) or

Firmicutes-dominated (36.5%) networks;

• The distribution of networks did not differ within any other

occupational class;

• Of interest, gut microbiota of various livestock species contain a high

relative abundance of the xylanolytic bacterial species Prevotella;

• Could transmission of microbes across host species explain the

protective effects of animal exposure on allergies and asthma?

AIRWAY MICROBIOME AND ASTHMA

(LEGATZKI ET AL., 2014)

• Several studies have shown that the

airways of asthmatics have an altered

bacterial composition compared to airways

of healthy airways

• A greater microbial richness and diversity

may be present in asthmatic airways i.e.

greater abundance of Proteobacteria and

Firmicutes.

• Birth cohort study suggested a role for

Streptococcus pneumonia, Haemophilis

influenzae, and M catarhalis in early life

(associated with asthma in later life;

Bisgaard et al., 2011)

• Data largely inconclusive (not many

studies have been conducted)


Novel intervention to prevent asthma?

DAMP HOUSING AND RESPIRATORY AND ALLERGIC

DISEASE: ISAAC PHASE II – WEINMAYR ET AL., 2013


No association between HDM allergen levels and symptoms


THE PROTECTIVE EFFECT OF RAW MILK CONSUMPTION ON ASTHMA AND

ATOPY (BRAUN-FAHRLANDER AND VON MUTIUS, 2010)

Reference Population Exposure Result

Riedler et al, 2001 Rural farm/non-farm children (n=812)

Milk directly from farm asthma, hayfever, atopy

Waser et al, 2007 Rural farm/non-farm children, steiner, peri urban (n=14,893)

Milk directly from farm

asthma, hayfever, atopy

Perkin and strachan, 2006

Rural farm/non-farm children (n=4767)

Unpasteurised milk eczema, atopy asthma

Barnes et al, 2001 Rural farm/non-farm children (n=929)

Unpasteurised milk

atopy

Radon et al, 2004 Rural farm/non-farm adults (n=321)

Raw, unboiled farm milk atopy

Wickens et al, 2002 Farm children/children from small towns

Unpasteurised milk atopic eczema


THE PROTECTIVE EFFECT OF FARM MILK CONSUMPTION ON CHILDHOOD

ASTHMA AND ATOPY: THE GABRIELA STUDY. (LOSS ET AL., 2011)

- Strongest associations with milk consumption commencing before the age of 1 yr

- No association with bacteria counts and fat content

EARLY LIFE NUTRITION SYMPOSIUM 2016

Brick et al., JACI, 2016


Brick et al., JACI, 2016

What about other co-exposures?


TRUCK TRAFFIC AND ATOPIC SENSITISATION IN DUTCH SCHOOL

CHILDREN LIVING NEAR BUSY MOTORWAYS JANSSEN ET AL., 2003


INHIBITION OF ENDOTOXIN-INDUCED PERINATAL ASTHMA

PROTECTION BY POLLUTANTS IN AN EXPERIMENTAL MOUSE MODEL

(REIPRICH ET AL., 2013)

RESPIRATORY CONFERENCE 1016


ENVIRONMENTAL ALLERGENS, PROTECTIVE FACTORS,

ADJUVANTS AND ALLERGY RISK

Protective

exposures

Adjuvant

exposures

“Normal” low risk e.g. farmers Intermediate risk

High risk e.g. inner city populations in the US?

High risk

ASTHMA AND THE ENVIRONMENT: HAVE WE MADE MUCH PROGRESS?


- Surprisingly/disappointingly little.

- Does allergen exposure play a major role in primary causation?

- Possibly not. Assuming that most people are exposed, protective and adjuvant

exposures determining the individual’s susceptibility to develop allergies and

asthma may be more important

- Microbial exposure: risk factor, protective, or both?

- Probably both. Effects may be dependent on dose, type, timing and asthma

phenotype

- What about other co-exposures?

- Current knowledge about interactions between allergen, protective and adjuvant

exposures is limited

- Options for prevention/intervention?

- Limited.

- Interventions to promote a healthy microbiome may be a promising approach.

- Identifying raw milk components that may be associated with protective effects

may provide useful clues.

JEROEN DOUWES NZ RESPIRATORY CONFERENCE 1016

Thank you

asthma: the role of the environment · 2016-12-05 · protective effect of infant infections •...

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