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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
NZ RESPIRATORY CONFERENCE 1016
Haahtela et al., 2013
ASTHMA AND THE ENVIRONMENT: EARLY LIFE
FACTORS
NZ RESPIRATORY CONFERENCE 1016
- Aero-allergens
- Microbial exposure: protective, risk factor or both?
- Raw milk: protective?
- Effect modification of co-exposures?
- Have we made any progress?
NZ RESPIRATORY CONFERENCE 1016
PIAMA BIRTH COHORT INTERVENTION STUDY GEHRING ET AL., ALLERGY 2012;67:248-256
NZ RESPIRATORY CONFERENCE 1016
- 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
NZ RESPIRATORY CONFERENCE 1016
- HDM levels at 3 months and symptoms at age 5.
PAULA BIRTH COHORT STUDY ILLI ET AL., ANN ALLERGY ASTHMA IMMUNOL 2014;112:132-139
NZ RESPIRATORY CONFERENCE 1016
- Endotoxin levels at 3 months and symptoms at age 5.
PAULA BIRTH COHORT STUDY ILLI ET AL., ANN ALLERGY ASTHMA IMMUNOL 2014;112:132-139
NZ RESPIRATORY CONFERENCE 1016
- 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
NZ RESPIRATORY CONFERENCE 1016
REDUCED MICROBIAL BIODIVERSITY: OLDER
SIBLINGS
NZ RESPIRATORY CONFERENCE 1016
Strachan., 1989 Birth cohort: 17,414 subjects
ENDOTOXIN EXPOSURE AT 12 MONTHS AND DOCTOR’S
DIAGNOSED ASTHMA AT 48 MONTHS (DOUWES ET AL., 2006)
NZ RESPIRATORY CONFERENCE 1016
ENDOTOXIN AND CHILDHOOD WHEEZE AND ASTHMA: A META ANALYSIS
MENDY ET AL., 2011
NZ RESPIRATORY CONFERENCE 1016
EFFECT OF ENDOTOXIN AND ALLERGENS ON NEONATAL
LUNG FUNCTION (ABBING-KARAHAGOPIAN ET AL., 2012)
NZ RESPIRATORY CONFERENCE 1016
• 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.
NZ RESPIRATORY CONFERENCE 1016
INDEPENDENT AND JOINT EFFECTS OF CURRENT AND PRENATAL ANIMAL EXPOSURE
IN NZ FARMERS’ AND RURAL REFERENCE CHILDREN - DOUWES ET AL., 2008
NZ RESPIRATORY CONFERENCE 1016
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
NZ RESPIRATORY CONFERENCE 1016
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364;8:2011
REDUCED GUT MICROBIAL BIODIVERSITY AND NCDS
NZ RESPIRATORY CONFERENCE 1016
• 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
NZ RESPIRATORY CONFERENCE 1016
- 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)
NZ RESPIRATORY CONFERENCE 1016
Novel intervention to prevent asthma?
DAMP HOUSING AND RESPIRATORY AND ALLERGIC
DISEASE: ISAAC PHASE II – WEINMAYR ET AL., 2013
NZ RESPIRATORY CONFERENCE 1016
No association between HDM allergen levels and symptoms
NZ RESPIRATORY CONFERENCE 1016
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
NZ RESPIRATORY CONFERENCE 1016
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
EARLY LIFE NUTRITION SYMPOSIUM 2016
Brick et al., JACI, 2016
NZ RESPIRATORY CONFERENCE 1016
Brick et al., JACI, 2016
What about other co-exposures?
NZ RESPIRATORY CONFERENCE 2016
TRUCK TRAFFIC AND ATOPIC SENSITISATION IN DUTCH SCHOOL
CHILDREN LIVING NEAR BUSY MOTORWAYS JANSSEN ET AL., 2003
NZ RESPIRATORY CONFERENCE 1016
INHIBITION OF ENDOTOXIN-INDUCED PERINATAL ASTHMA
PROTECTION BY POLLUTANTS IN AN EXPERIMENTAL MOUSE MODEL
(REIPRICH ET AL., 2013)
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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?
NZ RESPIRATORY CONFERENCE 1016
- 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