Paediatric Allergic respiratory disorders A bird s eye view Samudra Mukherjee
What are allergic immune responses really for? Ascaris Enterobious Hookworm Leishmania Onchocerca Plasmodium Schistosome Taenia Toxoplasma Trichuris Trypanosoma Wuchereria
Agenda What is atopyand allergy? Asthma as immunological disease Asthma as environmental disease Aero-allergens and food allergens. Clinical relevance of allergy in asthma. Management of allergic aspects of asthma. Can we prevent asthma?
Atopy A heritable tendency to produce excessive amount of IgEin response to foreign proteins
Allergy This is the clinical manifestation of atopy. Respiratory-Asthma, allergic rhinitis. Skin-Atopicdermatitis. Gastro-intestinal Food allergy
Normal larynx Laryngeal oedema
Asthma--an immunologic disease adaptive and innate immunity play major roles Asthma, as a complex trait, develops after environmental exposures, such as to innocuous. allergens, infectious agents, and air pollutants, in genetically susceptible individuals
The Fate of Immune Responses Depends on the Balance between Effector and Regulatory T cells T eff T reg
Revisiting the Th1-Th2 Paradigm IL-12 IFN-a Naïve CD4 IL-4 TGF-β Th1 Th2 TNF IFN-g Cell-mediated AUTOIMMUNITY Treg IL-4 IL-5 IgE ALLERGY éosinophilia
Neonatal & infant immune systems Serial infections Immune response Th1 Th2 Th2 Age The intrauterine environment is powerfully Th2 this imprints Th2 dominance upon the neonate Balanced Th1/Th2 at ~2yr
Delayed maturation of Th1 capacity Immune response Few serial infections hygiene, small family size etc Th1 Th2 Age Longer period of time in which to make and establish Th2 responses to environmental antigens (i.e. allergens) Unbalanced Th1/Th2 Th2 dominance at ~2yr
What does allergen do May do nothing. to the airways? Altered non-specific responses. Altered immunological milieu. Altered structural elements. (airways remodelling)
Key features of allergy? IgE antibodies Systemic Local Stereotyped pattern of inflammation Eosinophils, Mast cells T-lymphocytes Epithelial damage
Allergic vs Non-allergic asthma Parameter Allergic Non-Allergic Onset < 5yr Later Atopy Present Absent Sex Male>Female Female >Male Cell Eosinophil Neutrophil Treatment Easier Difficult
Asthma- an environmental disease Viral RTI. Food allergy. Aeroallergy Nonspecific irritants like cigarette smoke and air pollution
Wheezing prevalence at each time point to age 7 years for 6 phenotypes of wheeze
Prevalence of wheeze by age (All children with any wheezing episode age 5-7 years Atopic (n=94) Aeroallergen sensitization also associated with loss of lung function & AHR 1-5years, atopy =nonatopy Non-Atopic (n=59) MAS Study: Lancet 2006; 368: 763-70
Potent indoor aeroallergens Dust mite (Dermatophagoides pteronyssinus, D. farinae). Cat epithelium/dander (Felis domesticus). Dog epithelium/dander (Canis familarias). German cockroach (Blatella germanica). Mouse (Mus muscularus). Rat (Rattus norvegicus) and molds are known sources of.
Molds About 10% of the population have IgE antibodies to common inhalant molds. About half of these individuals (5% ) predicted to have allergic symptoms as a consequence of exposure to fungal allergens. Outdoor exposure is generally more relevant in terms of sensitization and disease than indoor fungal allergens.
Indoor vs outdoor molds Indoor molds-aspergillus, Penicillium. Cladosporium Both outdoor and indoor mold- Alternaria.
Fitted predicted probability curve for persistent wheezing by age 5 years in relation to the sum of mite, cat, and dog allergens derived from the logistic regression analysis
Association between lung function at age 5 years and a sum of mite, cat, and dog allergen-specific IgE antibodies (regression line with 95% CIs).
Food allergy and asthma-1 Food allergy is often linked with asthma in population based studies. Food allergy as a risk factor for lifethreatening asthma. Commonly implicated foods are-peanut, Cow s milk, Egg,Fish and Shrimp.
Food allergy and asthma-2 In one study, 100 small children with IgE-and Non-IgE-mediated milk allergy (mean age 16 months) were challenged with milk. Regardless of the immunological mechanism, one-fifth developed lower respiratory tract symptoms during the challenge.
Food allergy and asthma-3 In a larger study, 320 subjects (6 months to 30 years of age) with atopic dermatitis and possible food allergy underwent placebocontrolled, blinded food challenges. Food allergy was confirmed in 205 (64%) One-quarter experiencing lower airway problems during the food challenge.
The mechanism of food-induced asthma Food allergens are able to directly stimulate airway mast cells reaching there either inhalation or by aspiration inducing a lower airway reaction. Secondly, allergenic proteins may also be able to reach the lungs via the circulation, having been absorbed intact from the gut. A last possibility is that allergenic protein may act indirectly on the lower respiratory tract via inflammatory mediators released from the skin or gastrointestinal tract and circulating in the blood.
Allergy Epidemic is Environmental But Inconsistencies re. the Role of Environmental Exposures Breast Feeding Protects (Kull et al, JACI 2005;116:657-61) Increases the risk (Sears et al, Lancet 2002;360:901-7) Does not matter (Burgess et al, Pediatrics 2006;117:e787-92) Cat ownership Good (Hesselmar et al, CEA 1999;29:611-7) Bad (Noertjojo et al, JACI 1999;103:60-65) Does not matter (Rhodes et al, JACI 2001;108:720-5)
CD14 Pattern recognition receptor Part of receptor complex for endotoxin Soluble or membrane bound CD14 Activation of pathway IL12 allergy Maps to 5q32 -region of linkage to asthma. 3 alleles-cc, CT and TT Studies linking genetic variation and risk of asthma is extremely heterogenous and confusing
Predicted probability curves for allergic sensitization at 5 yr of age in relation to environmental endotoxin load in children with CC, CT, and TT genotypes in the promoter region of the CD14 gene
Asthma--a complex trait Develops after environmental exposures, such as to innocuous. allergens, infectious agents, and air pollutants, in genetically susceptible individuals
Development of Asthma A B C Antenatal Postnatal Anatomical (airway calibre) Viruses, pollution, others Immunological Genes: Ante and Postnatal Effects VIRUSES? ASTHMA
Theraputic options Environmental control. Biological agents. Immunotherapy Primary prevention.
D. pteronyssinus L. destructor D. pteronyssinus G. domesticus A. siro T. putrescentiae
Environmental Control of House Dust Mites First Line (Necessary and Cost Effective) Replace mattress and pillow encasements. Wash bed linen every 1 to 2 weeks, preferably in 60ºC. Remove stuffed toys. Regularly vacuum carpeted surfaces. Regularly dust hard surfaces. Reduce indoor relative humidity (dehumidify and do not add humidity)
Environmental Control of House Dust Mites Second Line (Helpful but More Expensive) Remove carpets, especially in the bedroom. Remove upholstered furniture. Avoid living in basements Third Line (Limited or Unproven Benefit) Acaricides. Tannic acid. Air cleaners
Environmental Control of Mold Allergens Identify sites/sources of mold growth. Clean moldy areas with a fungicide. If cleaning is not possible, discard moldy items (e.g. carpets, furniture). Dehumidify. Repair leaks and maximize drainage. Run vent in bathroom and kitchen. Clean refrigerator, dehumidifier, and humidifier with fungicide
Environmental Control of Animal Allergens Remove source (e.g. find a new home for the pet). Allergen levels fall slowly benefit would not be expected for weeks to months. Follow by aggressive cleaning to remove reservoirs of allergen. Possible role for tannic acid to augment allergen removal.
If the pet is not removed Install air cleaners, especially in the bedroom. Remove carpeting, especially in the bedroom. Replace mattress and pillow covers. Wash animals ( at least twice a week). May not be helpful in highly allergic patients.
Therapeutic principles Control of Environmental Factors that Affect Asthma Use the patient's medical history, skin testing or specific IgE to identify allergen exposures. If sensitized and exposed to allergens, reduction in allergen exposure helps all irrespective of asthma severity. Effective allergen avoidance needs a multifaceted, comprehensive approach. Consider immunotherapy in severe cases with clear evidence sensitization and deterioration with exposure.
Immunotherapy in asthma Allergen can be administered as either subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). Desensitisation is available for common aeroallergens such as pollen, house dust mite, and cat
Immunotherapy in asthma Effectiveness and utility remains controversial. SCIT may lead to a reduction in asthma symptoms, medication, and allergen-specific bronchial hyper-responsiveness (BHR). No consistent effect on lung function. SCIT inferior to inhaled corticosteroids in adults.
Immunotherapy in asthma SLIT is not currently approved for children. SCIT and SLIT studies have included patients with mild/moderate asthma and examined monotherapy, but not polytherapy with an allergen mixture. The risk of anaphylaxis with SCIT.
Immunotherapy-Indications Well documented mono or paucisensitive allergic asthma with reliable allergen extracts are available. Use immunotherapy in addition to appropriate environmental control and pharmacotherapy
Immunotherapy-Contraindications Polysensitization-Relative Age less than 3 years. Noncompliant Patients. Severe/unstable asthma
Specific immunotherapy has long term preventive effect of seasonal and perennial asthma: 10 year follow up on the PAT study Allergy Volume 62, Issue 8, pages 943-948, 6 JUL 2007 DOI: 10.1111/j.1398-9995.2007.01451.x http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2007.01451.x/full#f3
Rhinitis: Symptomatic disorder of the nose characterized by itching, nasal discharge, sneezing and nasal airway obstruction. Allergic rhinitis: Induction of rhinitis symptoms after allergen exposure by an IgE-mediated immune reaction; accompanied by inflammation of the nasal mucosa and nasal airway hyperreactivity.
Allergic Rhinitis phenotypes most common forms Infectious: Viral (acute), bacterial, fungal Non-Allergic, Non-Infectious, Rhinitis Non-Allergic Rhinitis with Eosinophilia Syndrome (NARES) Chronic Rhinosinusitis with or without Polyps: Hypertrophic, inflammatory disorder that can affect allergic or non-allergic individuals
Allergic rhinitis: impact High prevalence Impaired quality of life Work and school absence Impaired learning Impaired sleeping Associated asthma, sinusitis, otitis
Allergic rhinitis co-morbidities Conjunctivitis Sinusitis Otitis Media Cough Asthma
Allergic rhinitis classification Intermittent Persistent Symptoms Symptoms < 4 days / week > 4 days / week or < 4 weeks or > 4 weeks Mild Sleep: normal Daily activities (incl. sports): normal Work-school activities: normal Severe symptoms: no Moderate- severe Sleep: disturbed Daily activities: Restricted Work and school activities: disrupted Severe symptoms: yes
Allergy skin prick testing Skin prick test / positive result
Diagnosis of allergic rhinitis Detailed personal and family allergic history. Intranasal examination anterior rhinoscopy. Symptoms of other allergic diseases. Allergy skin tests and/or In vitro specific IgE tests
(a) The gross structural anatomy of the nasal mucosa; (b) the dense plexus of capillary venular microvessels just beneath the epithelial lining of the nasal mucosa. The major obstructive mechanisms in rhinitis are congestion and blood-filling of the venous sinusoids in the nasal passages.
The immediate (early phase) allergic reaction in the nose brain PRURITUS sensory nerves epithelium glands (mucous) SNEEZING blood vessels OBSTRUCTION RHINORRHEA histamine sulfidopeptide leukotrienes
Management of Allergic Rhinitis: ARIA Guidelines mild intermittent moderate severe intermittent intranasal steroid mild persistent moderate severe persistent oral or local nonsedative H1-blocker intranasal decongestant (<10 days) or oral decongestant leukotriene receptor antagonists avoidance of allergens, irritant and pollutants immunotherapy Modified from Bousquet J et al. J Allergy Clin Immunol. 2001;108:S147.
Agents and actions Oral antihistam ines Nasal antihistam ines Cys-LT1 receptor antagonists Nasal steroids Nasal decongest ants Oral decongest ants Nasal ipratropium Nasal cromones Rhinorrhea + + ++ ++ +++ 0 0 +++ + Congestion + + + +++ ++++ ++ 0 + Sneezing ++ ++ ++ +++ 0 0 0 + Pruritus ++ ++ + +++ 0 0 0 + Ocular symptoms ++ 0 ++ ++ 0 0 0 0 Onset of action 1 hr 15 min 48 hr 12 hr 5-15 min 1 hr 15-30 min - Duration 12-24 hr 6-12 hr 24 hr 12-48 hr 3-6 hr 12-24 hr 4-12 hr 2-6 hr Modified from van Cauwenberge P Allergy 2000;55:116-134