1.
Allergic rhinitis
(Part I)
Pannipa Kittipongpattana, M.D.
2 November 2018
Division of Allergy and Immunology , Department of Pediatrics
King Chulalongkorn Memorial Hospital

2.
Outline
 Definition and classification
 Epidemiology
 Pathophysiology and mechanisms
 Risk factors
 Evaluation and diagnosis
 Associated conditions
 Management

3.
Outline
 Definition and classification
 Epidemiology
 Pathophysiology and mechanisms
 Risk factors
 Evaluation and diagnosis
 Associated conditions
 Management

4.
First description of Hay fever
“ About the beginning or middle
of June in every year….
A sensation of heat and fullness is
experienced in the eyes….
…. To this succeeds irritation of
the nose producing sneezing….
….To the sneezing are added a
further sensation of tightness of the
chest, and a difficulty of breathing”
John Bostock, Med Chir Trans,1819; 10:161

5.
Definition
 Allergic rhinitis is an IgE-mediated inflammatory
nasal condition resulting from allergen introduction
in sensitized individual.
 The classic cardinal symptoms:
 Nasal congestion
 Rhinorrhea (usually clear and watery)
 Sneezing
 Pruritus of nose, palate, throat or ears

6.
ARIA Classification of Allergic rhinitis
(Old)
Seasonal AR
Outdoor allergens
Tree pollinate (spring)
Grasses (early
summer)
Weeds (late summer)
Perennial AR
Persistent
(year-round symptoms)
Indoor allergens
House dust mites
Animal dander
Molds
Cockroaches
Intermittent
(cyclical exacerbation)

7.
ARIA Classification of Allergic rhinitis
(New)
Intermittent
symptoms
< 4days/week
OR
< 4 weeks at a time
Persistent
symptoms
≥ 4days/week
AND
≥4 weeks at a time
Mild
Normal sleep
Normal daily activities
Normal work and school
No troublesome symptoms
Moderate-to-severe
One or more items
Abnormal sleep
Impairment of daily activities
Abnormal school or work
Troublesome symptoms

8.
Phenotypes
of
chronic
rhinitis
Hellings PW, Klimek L, Cingi C, et al.Allergy. 2017 Nov;72(11):1657-1665.

9.
Outline
 Definition and classification
 Epidemiology
 Pathophysiology and mechanisms
 Risk factors
 Evaluation and diagnosis
 Associated conditions
 Management

10.
Prevalence of allergic rhinitis in different regions of
the world, according to the Global Atlas of allergic
rhinitis
Adapted from Akdis et al. European Academy of Allergy and Clinical Immunology 2015.

11.
The Atopic March
J Allergy Clin Immunol 2017;139:1723-34.

12.
Outline
 Definition and classification
 Epidemiology
 Pathophysiology and mechanisms
 Risk factors
 Evaluation and diagnosis
 Associated conditions
 Management

13.
Pathophysiology
 Sensitization: development of specific IgE
 Allergens reach Antigen-Presenting Cells (APCs)
 APCs promote Th2 polarization
 Th2 promotes production of allergen-specific IgE
 Subsequent response: development of symptoms
 Nasal symptoms: Early & Late phase response
 Specific & non-specific hyperresponsiveness
 Lower airways symptoms (United airway hypothesis)

14.
Sensitization: Th2 Polarization
D
D
Th
0
MHC II
CD28CD80
CD86
Lymph
Proteas
e
Irritant
Toxin
Pathoge
n
damage activation
IL25
IL33
TSLP
IL
C
2
IL13
IL4
Nat Rev Immunol. 2009 Feb; 9(2): 125–
Th
2

15.
Sensitization: Specific IgE
Production
Nature Reviews Immunology volume3, pages721–

16.
Sensitization: Overview
IgE bounded
Basophil & Mast cell
FcɛRI
Middleton 8th edition

17.
Response to subsequent allergen
Nature Reviews Immunology volume3, pages721–

18.
Nature Reviews Immunology volume7, pages93–
Preformed mediators
- Histamine
- Tryptase
Synthesized
mediators
- PGD2
- Cysteinyl LT

19.
https://ipfs.io/ipfs/QmXoypizjW3WknFiJnKLwHCnL72vedxjQkDDP1mXWo6uco/wiki/Seratrodast.html
IL, LT, PAF, GM-
CSF, ICAM-1,
VCAM-1

20.
Nasal Hyperresponsiveness
 Specific hyperresponsiveness (Priming)
 Dose of allergen required to evoke response
 Non-specific hyperresponsiveness
 Capacity to response to various non-specific
substances

21.
Connell JT: Quantitative intranasal pollen challenge: III. The priming effect in allergic rhinitis. J Allergy 1969; 43:
Nasal Hyperresponsiveness

22.
United Airway Hypothesis
1. Mouth breathing
2. Aspiration
3. Nasobronchial reflex
4. Systemic spill
Proc Am Thorac Soc. 2009 Dec;6(8):652-4.

23.
Mouth breathing &
Bronchoconstriction
 Theory
 Nose function as filter
& air-conditioning
 Mouth breathing
bypass this filter and
result in
 Cold & dry air
 Unfiltered irritants &
allergens
J Appl Physiol (1985). 2000 Mar;88(3):1043-50.

24.
Mouth breathing & Asthma
Allergy. 2016 Jul;71(7):1031-6
- N = 9,804
- 17% of the population had Mouth breathing
- OR for asthma morbidity was
- mouth breathing alone 1.85 (95% CI, 1.27-2.62)
- AR alone 2.20 (95% CI, 1.72-2.80)
- when coexisted 4.09 (95% CI, 3.01-5.52)
Allergy. 2016 Jul; 71(7):1031-6.

25.
Aspiration of nasal content
 Theory: Post-nasal drip  aspirate  coughing
 However, nasal application of radioactive-
labeled allergen could not reach lower
respiratory tract
 Stimulation of pharyngolaryngeal receptors is
more likely to be responsible for a postnasal
drip-related cough
J Allergy Clin Immunol. 1997 Jul;100(1):122-9
Proc Am Thorac Soc. 2009 Dec;6(8):652-4.

26.
Nasobronchial reflex & Systemic
spill
 Q: Is there a neural reflex between nasal &
airway
Am Rev Respir Dis. 1990
Metacholine nasal spray
Asthma + AR subjects
lidocain
e
phenylephrin
e
Bronchoconstriction
J Allergy Clin Immunol. 1992
Study in asthma + AR
subjects

nasal provocation with
allergen

 bronchial responsiveness
to methacholine
at 30 minutes & 4.5 hours

27.
United Airway Hypothesis
1. Mouth breathing
2. Aspiration
3. Nasobronchial reflex
4. Systemic spill

28.
Outline
 Definition and classification
 Epidemiology
 Pathophysiology and mechanisms
 Risk factors
 Evaluation and diagnosis
 Associated conditions
 Management

29.
Risk factors for allergic rhinitis
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

30.
Genetics
Twin study
Support role of genetics
GWAS
Screen for association
Candidate gene study
Prove & explain
ISCAR: Allergic Rhinitis.Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

31.
Genome-Wide Association Study (GWAS)
Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis. Nat Genet. 2018 Aug;50(8):1072-1080.
Known association
Novel loci in study
Not carried forward
~ 41 loci found to be associated with AR
Their function involve in
- Regulation of B cell & T cell
- Antigen recognition
> Most strong signal: HLA-DQB1
> Overlapped with asthma, eczema,
autoimmune diseases, and also non-
allergic rhinitis

32.
Inhalant allergens
Pollens
Mites
Fungal allergens
Animal dander
ISCAR: Allergic Rhinitis.Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

33.
Pollens: PRO
The Melbourne Atopy Cohort Study (MACS): 620 babies with atopy in family
Pollens exposure & AR development
OR (95%CI)
First 3 months 1.14 1.01-1.29
First 6 months 1.11 1.01-1.21
Clin Exp Allergy. 2013 Mar;43(3):337-43.
Adjusted for gender and family history of atopy

34.
Pollens: only associated with Asthma and Sensitization
Unusually high birch pollen in 1993 → study in children with atopy in family
J Allergy Clin Immunol. 2002 Jul;110(1):78-84.

35.
Mites
ISCAR: Allergic Rhinitis.Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

36.
Fungal allergens
Most studies showed fungal allergens as a risk factor for AR development
But some studies found no association with AR
Animal dander
Results are very conflicting regarding pets and development of AR
Many variables: pet age, gender, and species; number of household pets;
home characteristics; atopic predisposition of the pet owners
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

37.
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

38.
Food allergens: Questions
?
?
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

39.
Food allergens: food sensitization
Allergy. 2016 Jan;71(1):77-89.
Food sensitization
↑allergic rhinitis

40.
Food Allergens: in utero food exposure
Avoidance of milk, egg, peanut during
pregnancy, lactation, and infancy to
reduce allergy
NOT SIGNIFICANT
Lower milk and egg ingestion in 3rd
trimester to reduce allergy
NOT SIGNIFICANT
Avoidance of milk and egg after GA 28w to
reduce allergy
NOT SIGNIFICANT+LBW+Preterm
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
Evidence for the effects of food allergen exposure on the development of AR

41.
Pollution: theory
NO₂, SO₂, CO, O₃ Damage epithelium
Carry allergen

42.
Pollution: Cohort studies showed no correlation
Study limitations
- Many confounders: socioeconomic status, background pollutant, type of pollutant
- Accuracy of pollution level measurement
- Geographic diversity
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

43.
Tobacco Smoke: theory
Damage
epithelium
Epigenetic
mechanism
Immune
suppression

44.
Tobacco Smoke
PLoS Med. 2014 Mar 11;11(3):e1001611.
0.92-1.15 1.06-1.15

45.
Tobacco Smoke
PLoS Med. 2014 Mar 11;11(3):e1001611.
“Weak association between smoke
exposure and allergic disease in
adults but suggest that both active
and passive smoking are associated
with a modestly increased risk of
allergic diseases in children and
adolescents.”

46.
Socioeconomic Status (SES)
The oldest and the most controversial risk factor
A proxy of
- Siblings number
- Breast feeding
- Diet
- Housing
- Overall hygiene
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

47.
Risk factors for AR
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

48.
Protective factors against allergic
rhinitis
 Breastfeeding
 Childhood exposure to pets
 Hygiene (biodiversity or microflora) hypothesis
 Number of siblings
 Farming
 Bacterial endotoxin
 Microbial diversity
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

49.
Breastfeeding
?

50.
Does breastfeeding protect against allergic rhinitis during childhood?
A meta-analysis of prospective studies
The horizontal bars represent the 95% confidence intervals
(CI).
The vertical lines represent the OR for each study.
Mimouni Bloch et al. Acta Paediatr. 2002;91:275–
Protective effect close to statistical significance in the general population
but not in children with a family history of atopic disease

51.
Breastfeeding and asthma and allergies:
a systematic review and meta-analysis
Lodge CJ, Tan DJ, Lau MX, et al. Acta Paediatr. 2015;104:38–53.

52.
Childhood exposure to pets
 The association of petkeeping in childhood
with the subsequent development of AR is
more controversial, and difficult to establish.

53.
ISCAR: Allergic Rhinitis.
Int Forum Allergy Rhinol.
2018 Feb;8(2):108-352.

54.
Hygiene (biodiversity or microflora)
hypothesis
 Number of siblings
 Farming
 Bacterial endotoxin
 Probiotics
 Microbial diversity

55.
Number of siblings
Karmaus W, Botezan C. J Epidemiol Community Health. 2002;56:209–

56.
Association of symptoms and disease labels with total
and older siblings, before and after adjustment for
covariates
Clin Exp Allergy. 2015 Jan; 45(1): 126–
OR for Hay fever Unadjusted Adjusted
Total siblings 0.92 (0.92-0.95) 0.92 (0.92-0.95)
Older siblings 0.91 (0.89-0.93) 0.91
(0.88-0.94)
sex, region, language
national GNI per capita

57.
Farming
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

58.
Bacterial endotoxin
 Exposure to bacterial endotoxin has been
studied as a possible protective factor.
 Inverse association between exposure to
endotoxin in
infancy and childhood
 the development of allergic sensitization has been
shown in rural and urban environments
 the results have not been uniform between the
studies.

59.
Bacterial endotoxin
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

60.
Forest plot of comparison: 1 Probiotics in pregnant women, outcome: Allergic rhinitis
Cuello-Garcia CA, Brozek JL, Fiocchi A, et al. J Allergy Clin Immunol. 2015;136:952–961.
Probiotics

61.
Forest plot of comparison: 1 Probiotics in breastfeeding mothers, outcome: Allergic rhinitis
Cuello-Garcia CA, Brozek JL, Fiocchi A, et al. J Allergy Clin Immunol. 2015;136:952–961.
Probiotics

62.
Forest plot of comparison: 1 Probiotics in infants, outcome: Allergic rhinitis
Cuello-Garcia CA, Brozek JL, Fiocchi A, et al. J Allergy Clin Immunol. 2015;136:952–961.
Probiotics

63.
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
Microbial
diversity

64.
Potential protective effect on the development
of AR
ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.

65.
Outline
 Definition and classification
 Epidemiology
 Pathophysiology and mechanisms
 Risk factors
 Evaluation and diagnosis
 Associated conditions
 Management