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HOW EFFECTIVE IS PREVENTION IN ASTHMA?. Dr. A. Füsun Kalpaklıoğlu. Environ ment. Genetics. Age. Environmental Influences Cigarette smoking in pregnancy increases the risk of wheezing in infancy

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HOW EFFECTIVE IS PREVENTION IN ASTHMA?

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HOW EFFECTIVE IS PREVENTION IN ASTHMA?

Dr. A. Füsun Kalpaklıoğlu


Environ

ment

Genetics

Age

Environmental Influences

  • Cigarette smoking in pregnancy increases the risk of wheezing in infancy

  • Allergen specific T-helper cell programming is initiated early in life and is driven by ubiquitos dietary and inhalant allergens

  • Early exposure to high levels of dietary allergens results in high zone tolerance

  • Exposure to low levels of inhalant allergens triggers low zone tolerance with weak Th1-like immunity or Th2 polarised response.

  • Some early respiratory infections, e.g. pertussis and RSV, may enhance IgE-sensitization

  • Relatively lack of early microbial exposure may enhance the development of allergic diseases.

Genetics

  • The atopic constitution is a major risk factor for the development of IgE-sensitization

  • Individuals with a family history of atopy have an increased risk of developing allergic diseases

  • Double heredity means a four-fold, Single heredity means a two-fold risk to develop allergies

  • Target organ sensitivity is a familial trait

  • High IgE level in cord blood is specific for subsequent allergic disease but has a low sensitivity

  • Early signs of atopic eczema, and presence of IgE antibodies to inhalant allergens, are important risk factors for later respiratory allergy

    ADAM 33 gene


Allergens

Microbes

Infections

Pollution

Stress

Cytokine response profile

Environ

ment

Genetics

Age

Prevention of allergen-specific IgE response,

sensitization

Primary prevention

Immune Response

Atopy Th2

Th1

Prevention of asthma in sensitized individual

Secondary prevention

  • Viral infections

  • Aeroallergens

  • Pollution

Lower airway injury

Prevention of the onset of symptoms in an asthmatic individual

  • Persistant inflammation

  • BHR

  • Remodelling

  • Lung maturation/differentiation

Abnormal repair

Tersiary prevention

ASTHMA


CYTOKINE BALANCE

ENVIRONMENT

ENVIRONMENT


Breast-feeding

  • The association between infant feeding practices and subsequent atopy among children with a family history of asthma

  • A cohort of children with a family history of asthma in Sydney, Australia, was followed from birth to age 5 years.

  • In 516 children evaluated at age 5 years, there was no significant association between the duration of breastfeeding or timing of introduction of solid foods and protection against asthma or other allergic disease.

  • However, breastfeeding for 6 months or more and introduction of solid foods after 3 months were both associated with an increased risk of atopy at age 5 years.

  • Longer duration of breastfeeding and later introduction of solid foods did not prevent the onset of asthma.

Mihrshahi S, CAPS Team. Clin Exper Allergy May 2007

Kull I, et al. JACI 2004;114:755-60.


The Link Between Housing & Health


NHLBI Report 2007


Effectiveness of the Mite Avoidance Intervention

Asthma and Wheezing at Age 5 by Mite AvoidanceTreatment

Marks et al, JACI 2006; 118:53


Asthma by Size of Alternaria Skin Test Responses at Age 6 in Tucson, AZ

p<0.00001

%

Asthma

Alternaria Response


Hygiene Hypothesis; Lack of intense infections in industrialized countries owing to improved hygiene, vaccination, and use of antibiotics may alter the immune system such that it responds inappropriately to innocuous substances. (increased allergy/asthma)


Atopic disease is the price paid by some members of the white community [as opposed to native Americans in Saskatchewan, Canada]

-Gerard JW, 1976


HYGIENE HYPOTHESIS


Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe

  • Cross sectional multi-centre study (PARSIFAL) including 14 893 children aged 5–13 years from five European countries (2823 from farm families and 4606 attending Steiner Schools as well as 5440 farm reference and 2024 Steiner reference children).

  • Farm milk consumption ever in life showed a statistically significant inverse association with asthma. The associations were observed in all four subpopulations and independent of farm-related co-exposures. Other farm-produced products were not independently related to any allergy-related health outcome.

Unpasteurized milk: health or hazard?

Waser M, et al. Clin Exper AllergyMay 2007


Endotoxin Exposure and IgE Mediated Sensitization

1.0

0.8

0.6

Predicted probability for sensitisation

P=0.005

0.4

0.2

0.0

1.0

2981

7.4

54.6

22000

162755

403.4

1.2x106

Endotoxin Load (EU/m2)

Simpson et al, AJRCCM September 2006


Endotoxin in inner-city homes: Associations with wheeze and eczema

Perzanowski M et al. JACI 2006;117:1082-9


Response to endotoxin increases with BMI

Obesity&Asthma

1.Development in early life

2.Mechanical factors promote asthma

3.GER resulting from obesity induces asthma

Alexis N et al. JACI 2006;117:1185-6


  • Data not to support the H.H.

  • Pets

  • Brussee JE et al.Allergen exposure at 3 m and

  • sensitization, wheeze and asthma at 4 y of age.

  • JACI 2005;115:946-52.

  • 4146 children from the Prevention and Incidence of Asthma and Mite Allergy study.

  • Early cat allergen exposure leads to persistent wheeze.

  • Early dog allergen exposure leads to persistent wheeze in children with maternal atopy.


Timing?

Having cat before age 18 protects against adult asthma&atopy!de Meer Gea, et al. Jacı 2004;113:433-8.


Probiotics; beneficial microbes in the gut flora may promote maturation of the immune system away from proatopic state


Probiotics: Lactobacillus&Bifidobacterium

Rautava S et al. JACI 2002;109:119-21


NHLBI Report 2007


ISLE OF WIGHT

Arshad et al. JACI 2007;119:307-13


The Canadian Study: 2 years

Becker, et al. JACI 2004;113:650-6


The Canadian Study: 7 years

Chan-Yeung et al. JACI 2005;116:49-55


The Childhood Asthma Prevention Study (CAPS), Sidney Australia

  • Established in 1997

  • Primary aims were to test whether in children at high risk of allergic disease the incidence of allergy and asthma at age 5 years could be reduced by the implementation of interventions directed at avoidance of HDM allergens, diet supplementation with omega-3 fatty acids, or a combination of these 2 interventions

Mihrshahi et al, JACI 2003;111:162-8

Marks GB et al. JACI 2006;118:53-61


成年人過敏性哮喘或鼻炎

哮喘/

鼻炎/濕疹

鼻炎

喘嗚/

哮喘

因食物引起的

過敏症狀

濕疹

誘發過敏

激發過程

連鎖過敏反應 (Allergy March)

若在嬰幼兒期間已誘發過敏感機制 (Sensitization)及出現過敏症狀, 他們在成長過程中可能會增加患上其他過敏症的風險

(Sarrinen U.M. & Kajosaari 1995; Bergmann RL et al. 1998 ; Host A 2001 ;Spergel JM & Paller AS 2003 ;Rhodes et al. 2001; Sampson H.A. 2003 ; Halken S 2004; Wickman M. 2005; Hahn E. & Bacharier L.B. 2005)


PEAK (Prevention of Early Asthma in Kids): Study Design

Treatment

Observation

Screening/

Eligibility

Run-in

Year 3

1 month

Years 1 & 2

Interim Efficacy Tests

Randomize

  • Randomized, multicenter, double-blind, parallelgroup, placebo-

  • controlled trial

  • 285 two and three year olds at high-risk for asthma

  • Fluticasone 44 g/puff or placebo (2 puffs b.i.d.)

Guilbert et al, NEJM 2006;354:1985


Episode-free Days During the Entire Study

Observation

Treatment

Guilbert et al, NEJM 2006;354:1985


ICS Effect During Treatment Phase

Asthma Exacerbations

P<0.001

Guilbert et al, NEJM 2006;354:1985


ETAC

EPAAC

Warner JO et al. JACI 2001;108:929-37


Immunotherapy; Mechanisms

IL-2

INF-g

Th1

IMMUNE DEVIATION?

ANERGY?

BOTH?

IT

TCD4+

Th2

IL-4

IL-5

IL-9


IT: Prevention of New Sensitizations

New sensitizations after 3 years:

55% SIT group vs 100% control group.

Des Roches et al, JACI 1997

New sensitizations after 3 years:

25% SIT group vs 67% control group.

Pajno et al, Clin Exp Allergy 2001

New sensitizations after 4 years

23% SIT group vs 68% control group.

Purello D’Ambrosio et al, Clin Exp Allergy 2001


Specific immunotherapy prevents the development

of asthma in children with allergic rhinitis

(the PAT study)

No asthma

%

Asthma

60

40

205 children with rhinitis

age: 6-14 yrs

grass or birch allergy

3 yrs immunotherapy

32

19

SIT

CONTROL

Moller C et al, JACI 2002

Niggemann et al, Allergy 2006;61:855-9


Asthma Treatment

moderate persistent asthma

intermittent asthma

mild persistent asthma

severe persistent asthma

allergen avoidance

pharmacotherapy

immünotherapy


Reduce Exposure to Triggers


Encasing Mattress

Halken S et al. JACI 2003;111:169-76


ARIA UPDATE


NHLBI Report 2007


NHLBI Report 2007


Asthma Treatment and Asthma Prevention: a Tale of 2 Parallel Pathways

Martinez FD 2007, JACI, in press


Two (Provocative) Ideas

  • Asthma-related airway remodeling and deficits in lung function growth occur mainly during the preschool years; blocking the processes that cause these changes will drastically reduce persistent asthma

  • In children with mild (moderate?) persistent asthma, intermittent, SABA-linked controller therapy may be as effective as daily therapy with ICS, and will be much more acceptable for parents and children alike

Martinez FD


Nature begins with the cause

and ends with the experience;

we need to operate in the reverse.-Leonardo da Vinci, 1512

THANK YOU!


Preventive MeasuresGuidelines

Primary prevention

  • Avoid smoking and Environmental Tobacco Smoke, particularly during pregnancy and early childhood (B). Remove tobacco smoke from work places (B)

  • Avoid damp housing conditions (C) and reduce indoor air pollutants (C)

  • Breast-feed exclusively until 4-6 months (B*). No special diet for lactating mothers (A)

  • Reduce exposure to inhalant allergens in young children at high risk

  • Eliminate sensitizing and highly irritating agents in occupational environments (C). Implement measures to prevent employee exposure

    * WHO: exclusive breast-feeding for 6 months in general


Preventive MeasuresGuidelines

Secondary prevention

  • Treat atopic eczema topically, and possibly with systemic pharmacotherapy to prevent respiratory allergy (D)

  • Treat upper airways disease (rhinoconjunctivitis, sinusitis) to reduce risk of asthma (D)

  • In young children sensitized to mites, pets or cockroaches, exposure should be reduced to prevent onset of allergic disease (B)

  • Remove employees from occupational exposure if they have symptoms caused by occupational allergic sensitization (C)


Preventive MeasuresGuidelines

Tertiary prevention

  • Infants with cow’s milk allergy avoid cow’s milk proteins; if a supplement is needed, use hypoallergenic formula, if available/affordable, to improve symptom control (B)

  • Patients with asthma, rhinoconjunctivitis or eczema, who are allergic to indoor allergens, should eliminate or reduce the exposure to improve symptom control and prevent exacerbations(A-B)

  • Environmental Tobacco Smoke aggravates asthma

  • Aim pharmacotherapy primarily towards the underlying inflammatory process (A)

  • Avoid strictly ASA and other non-steroidal anti-inflammatory drugs (NSAID) in patients who are sensitive to them (C)


Preventive MeasuresFurther actions for occupational allergies

  • Risks of occupational allergy should be monitored and epidemiological information collected by a globally agreed questionnaire

  • High risk allergy environments should be identified. In atopic employees who work in these environments, detection of sensitization by Skin Prick/Puncture Tests or IgE antibody measurements could prevent development of clinical allergy

  • General principles of prevention of occupational allergies should be published by national regulatory and advisory authorities


Lung Function at Age 7 by Sensitization and Exposure to Aeroallergens at Age 3

FEV1

Ratio

FVC

Illi et al, 2006; Lancet 368:763


Allergen Exposure

Genetic Predispositionto Allergies

Allergy,No Asthma

Sensitization

Genetic Predispositionto Asthma

Asthma


FEV1/FVC Ratio by Skin Test at Age 6

p<0.001

p=0.01

p=0.01

%


Maturation of Immune Responses in Infancy

Non-Allergic

Interferongamma

responses(Th1)

Allergic

24-36

0

Age (months)


ICS Effect on IOS Measures:Reactance at 5 Hz

p=0.008 p=0.83

Guilbert et al, NEJM 2006;354:1985


Busse PJ et al. JACI 2005;116:146-52


Experimental LPS/Allergen Exposure

Wang Y et al. JACI 2006;118:143-51


Experimental LPS/Allergen Exposure

Wang Y et al. JACI 2006;118:143-51


Encasing Mattress

Halken S et al. JACI 2003;111:169-76


Hijyen hipotezi


Long-lasting effect of sublingual immunotherapy

in children with asthma due to house dust mite:

a ten-year prospective study

V.Di Rienzo,Clin Exp Allergy, 2003

35 SLIT +

drugs

60

No More SLIT

pts

25 only

drugs

0

5

YEARS

10


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