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Allergic rhinitis 2
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Allergic rhinitis (part1)

  1. 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. 2. Outline  Definition and classification  Epidemiology  Pathophysiology and mechanisms  Risk factors  Evaluation and diagnosis  Associated conditions  Management
  3. 3. Outline  Definition and classification  Epidemiology  Pathophysiology and mechanisms  Risk factors  Evaluation and diagnosis  Associated conditions  Management
  4. 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. 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. 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. 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. 8. Phenotypes of chronic rhinitis Hellings PW, Klimek L, Cingi C, et al.Allergy. 2017 Nov;72(11):1657-1665.
  9. 9. Outline  Definition and classification  Epidemiology  Pathophysiology and mechanisms  Risk factors  Evaluation and diagnosis  Associated conditions  Management
  10. 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. 11. The Atopic March J Allergy Clin Immunol 2017;139:1723-34.
  12. 12. Outline  Definition and classification  Epidemiology  Pathophysiology and mechanisms  Risk factors  Evaluation and diagnosis  Associated conditions  Management
  13. 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. 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. 15. Sensitization: Specific IgE Production Nature Reviews Immunology volume3, pages721–
  16. 16. Sensitization: Overview IgE bounded Basophil & Mast cell FcɛRI Middleton 8th edition
  17. 17. Response to subsequent allergen Nature Reviews Immunology volume3, pages721–
  18. 18. Nature Reviews Immunology volume7, pages93– Preformed mediators - Histamine - Tryptase Synthesized mediators - PGD2 - Cysteinyl LT
  19. 19. https://ipfs.io/ipfs/QmXoypizjW3WknFiJnKLwHCnL72vedxjQkDDP1mXWo6uco/wiki/Seratrodast.html IL, LT, PAF, GM- CSF, ICAM-1, VCAM-1
  20. 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. 21. Connell JT: Quantitative intranasal pollen challenge: III. The priming effect in allergic rhinitis. J Allergy 1969; 43: Nasal Hyperresponsiveness
  22. 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. 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. 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. 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. 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. 27. United Airway Hypothesis 1. Mouth breathing 2. Aspiration 3. Nasobronchial reflex 4. Systemic spill
  28. 28. Outline  Definition and classification  Epidemiology  Pathophysiology and mechanisms  Risk factors  Evaluation and diagnosis  Associated conditions  Management
  29. 29. Risk factors for allergic rhinitis ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  30. 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. 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. 32. Inhalant allergens Pollens Mites Fungal allergens Animal dander ISCAR: Allergic Rhinitis.Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  33. 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. 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. 35. Mites ISCAR: Allergic Rhinitis.Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  36. 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. 37. ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  38. 38. Food allergens: Questions ? ? ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  39. 39. Food allergens: food sensitization Allergy. 2016 Jan;71(1):77-89. Food sensitization ↑allergic rhinitis
  40. 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. 41. Pollution: theory NO₂, SO₂, CO, O₃ Damage epithelium Carry allergen
  42. 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. 43. Tobacco Smoke: theory Damage epithelium Epigenetic mechanism Immune suppression
  44. 44. Tobacco Smoke PLoS Med. 2014 Mar 11;11(3):e1001611. 0.92-1.15 1.06-1.15
  45. 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. 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. 47. Risk factors for AR ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  48. 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. 49. Breastfeeding ?
  50. 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. 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. 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. 53. ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  54. 54. Hygiene (biodiversity or microflora) hypothesis  Number of siblings  Farming  Bacterial endotoxin  Probiotics  Microbial diversity
  55. 55. Number of siblings Karmaus W, Botezan C. J Epidemiol Community Health. 2002;56:209–
  56. 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. 57. Farming ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  58. 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. 59. Bacterial endotoxin ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  60. 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. 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. 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. 63. ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352. Microbial diversity
  64. 64. Potential protective effect on the development of AR ISCAR: Allergic Rhinitis. Int Forum Allergy Rhinol. 2018 Feb;8(2):108-352.
  65. 65. Outline  Definition and classification  Epidemiology  Pathophysiology and mechanisms  Risk factors  Evaluation and diagnosis  Associated conditions  Management

Hinweis der Redaktion

  • 10% - 40%, depending on geographic location
    Highest incidence occurring in children


    Allergic rhinitis affects up to 40% of the global population. It is
    present in more than 20% of people in the United Kingdom, and
    denotes a major cause of morbidity that affects the quality of life of
    individuals. The prevalence of AR in Europe is highest in Belgium (29%) [6]. Rhinoconjunctivitis symptoms are higher in high vs low income nations [7] (Fig. 2). In England, 10% of children aged 6 and 7 years and 15e19% of 13 and 14 year olds have allergic rhinitis. The International Study of Asthma and Allergies in Childhood (ISAAC study) stated an average prevalence of allergic rhinitis in 8.5% (1.8e20.4%) of 6e7 year olds and 14.6% (1.4e33.3%) in children aged between 13 and 14 years [3]. The likelihood of receiving a diagnosis of AR progresses with age in younger individuals but declines in the mid-20s. Allergic rhinitis globally is on the rise in most areas with few exceptions. According to the World Allergy Organization, Australia, New Zealand and the United Kingdom are countries with a very high prevalence of AR. Conversely, countries with a very low prevalence include Albania, Indonesia, Georgia, Romania and Greece [8].
  • The atopic march. AD prevalence peaks early in infancy, opening the door for consequent development of the atopic march. Development of FA, asthma, and allergic rhinitis in the young toddler age group is common after cutaneous manifestations. (J Allergy Clin Immunol 2017;139:1723-34.
  • การกระตุ้น IgE Class switching ต้องอาศัย signal สำคัญ 2 อย่างคือ
    IL-4 (หรือ 13)  activate STAT6
    CD40 ligand  activate Nuclear factor Kappa B
    STAT6 + NFKB induce Ie exon & AID: Activation-induced cytidine deaminase promoter
  • มาดูภาพรวมกันอีกทีค่ะ สรุปว่ากระบวนการ sensitization ก็เริ่มจาก...
    โดยสุดท้ายนอกจากได้ specific IgE ออกมาแล้วนั้น IgE ยัง bind อยู่กับ cell ต่างๆ โดยเฉพาะ Mastcell และ Basophil
  • Cell อื่นๆ ก็จับกับ Allergen ได้ไวขึ้น
    Cross link ของ IgE บน Mast cell นำไปสู่การ degranulation และหลั่ง cytokine ต่างๆ และนำไปสู่อาการ
  • อาการแบ่งออกเป็น early และ late response
  • ในคนไข้ Asthma ถ้าหายใจทางปากในอากาศเย็น FEV1 จะ drop ลงเร็ว แสดงให้เห็นว่าการ by pass อากาศไม่ผ่านจมูก มีผลจริงๆ
  • Questionnaire cohort ดู self-report AR , mouth breathing กับการเกิด Asthma (เข้า full text ไม่ได้ ไม่ทราบอายุเฉลี่ย แต่น่าจะเป็นผู้ใหญ่-วัยรุ่น)
  • Lidocaine เป็น nerve blocker ไม่ block การเกิด bronchoconstriction
    Phenyleprine เป็น vasoconstrictor block การเกิด bronchoconstriction ได้
    แสดงให้เห็นว่า Naso – Bronchial reaction นั้นถูกเชื่อมกันผ่านทางเลือด ไม่ใช่ nerve
  • a meta-analysis of prospective studies evaluating the effects of exclusive breastfeeding for the first 3 months of life on the development of AR.

    Six prospective studies met the inclusion criteria. In their pooled analysis, they found a protective effect of exclusive breastfeeding for the first 3 months of life that approached statistical significance in the general population (OR 0.74; 95% CI, 0.54 to 1.01).

    Interestingly, the protective effect was not seen in childrenwith a family history of atopic disease (OR 0.87; 95% CI,0.48 to 1.58).
  • There is some evidence that breastfeeding is protective for asthma (5-18 years). There is weaker evidence for a protective effect for eczema ≤2 years and allergic rhinitis ≤5 years of age, with greater protection for asthma and eczema in low-income countries.

    While the authors of
    this meta-analysis argued for the benefit of breastfeeding in
    the prevention of AR, they do acknowledge that the protective
    effect of breastfeeding seen in patients less than 5 years
    of age may have been confounded by known protective effects
    of breast milk against viral respiratory infections. The
    authors hypothesized that, given the difficulty of differentiating
    between AR and viral rhinitis in young children, a reduction in viral respiratory infections have been possibly
    interpreted as a reduction in rhinitis symptoms.
  • The impact of pet avoidance on AR development is best evaluated via longitudinal birth cohort studies.
    A systematic review of 9 studies conducted solely in urban environments
    evaluated perinatal pet exposure.642
    Six studies found that exposure to dogs, or cats/dogs protected against allergic
    disease.
    Two studies found increased risk of allergy only in highly atopic families. Furthermore, in a cohort of 620 children with family history of allergic diseases, exposure to cats or dogs was protective only in children with nonallergic fathers.534
  • Of the 17 studies that reported a result on hay fever in relation to siblings, all found a significant negative relation (fig 3,
    table 1). The odds ratios vary between 0.20 and 0.65 for three or more siblings versus no siblings.1 8 12–19 26 29 33 37–39 42 43
    Lewis et al reported associations for four children and more.17 23 Taylor et al found a prevalence ratio of 6% for the oldest and of 3.4%
    for children with older siblings (table 1), but did not provide the actual number of siblings.19 Some of the studies reported
    the results separately for older and younger siblings.8 42
    In this case, the effect of older siblings was stronger than the effect of
    younger siblings (fig 3).
    Of the 17 studies, eight had a cross sectional design, and nine a cohort design. Again, the weighted average was influenced by the large sample size of the Swedish study.
    Therefore, the weighted odds ratio including this study was 0.56. The odds ratio without the Swedish sample was 0.44.
  • A large study based on questionnaire data for children aged 6 to 7 years from 31 countries and 13 to 14 years from 52 countries confirmed that the inverse association between the number of older siblings and prevalence of hay fever was strongest in more affluent countries.

    In both age groups, inverse trends (P < 0.0001) were observed for reported ‘hay
    fever ever’ and ‘eczema ever’ with increasing numbers of total siblings, and more specifically
    older siblings. These inverse associations were significantly (P < 0.005) stronger in
    more affluent countries.

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