By: Dr. Hatim Ahmed Hassan Senior Registrar Pediatric ICU

Objective Prevalence and definitions Path physiology Types of allergies Mechanism of allergies History and Examination Diagnosis & management Common allergy diseases Conclusion

ALLERGIES IN CHILDREN Present 3-15%, 3 million active cases 2025 expected 50% next pandemic after metabolic x, diabetes, obesity The term allergy refer to patients who express an “ alter state of reactivity”

Hypersensitivity – objectively reproducible symptoms or signs following exposure to a defined stimulus (e.g. food, drug, pollen) at a dose which is tolerated by normal people. Allergy – a hypersensitivity reaction initiated by specific, immunological mechanisms. This can be IgE mediated (e.g. peanut allergy) or non-IgE mediated (e.g. coeliac disease). Atopy – a personal and/or familial tendency to produce IgE antibodies in response to ordinary exposures to potential allergens, usually proteins. Strongly associated with asthma, allergic rhinitis and conjunctivitis, eczema and food allergy. Anaphylaxis – a serious allergic reaction that is rapid in onset and may cause death

PREVALENCE Every third person in this room suffers from some kind of allergy (66%) One Third have multiple forms. Ingestants, Contacts, Inhalents, Haptens, Injectants etc Only 30% GP, treat as per any protocol.

Immunological fashions in Medicine 1960’s & 1970’s : Immunoglobulin E 1970’s & 1980’s : Mast cells & Eosinophils 1980’s & 1990’s :Environment – ante-natal & adult, allergens, Th2 cells 1990’s & 2000’s :Microbial experience, Epithelium  Although undoubtedly a useful model, the textbook ‘skew to Th2’ model is too simplistic to explain allergy  Allergy is a disease of impaired immune regulation  Where is the regulatory lesion?

Allergy is a systemic disorder Nose Pharynx Stomach Oesophagus Lungs “Global diseases” – due to the large spectrum of symptoms affecting the whole body Skin Food allergy Allergic rhinitis Asthma EczemaUrticaria Allergic dermatitis

Key Elements (6) 1. Allergens 2. T Cells 3.Antigen Presenting Cells (APC) 4. IgE and its receptors 5. Eosinophil 6. Mast Cells

1. ALLERGENS An allergen is something that triggers an IgE response in genetically predisposed individuals. Molecular weight Kilodaltons (kDa). Whereas allergens 70 kDa do not pass the mucus membrane barrier.

2.T Cells  Babies are usually sterile at birth after which they are exposed to allergens and Infections.  A Th-1 response produces cytokines that promote phagocytosis  Th-2 cells are induced in genetically susceptible atopic individuals that secrete cytokines favoring IgE synthesis.  These cytokines IL4 and IL13 act on Eosinophils, Mast cells and Basophils that leads to an outpouring of Histamine 1,2, and 3.

In-vitro differentiated monocyte-derived Dendritic Cell 3.Antigen Presenting Cells (APCs)  The following cells are APCs  Dendritic Cells  Langerhan Cells  Monocytes  Macrophages These carry either a DC 1, which promotes Th-1 and no allergy. In atopic individuals they carry DC 2 surface protein that causes Th-2 production and the allergy cascade.

4-IgE and its receptors Fc epsilon R1 and Fc epsilon R2 (CD23) bind to the Alpha chain of the IgE molecule. These are present on all APC cells. Cross linking of receptor bound IgE molecule initiate a complex intracellular leading to a release of various mediators of Inflammation

5.Eosinophils  The degranulation of Eosinophils releases  1. Major Basic Protein  2. Eosinophil derived neurotoxin  3. Peroxidase  4. Cationic proteins  These cause damage to epithelial cells  Induce airway hyper responsiveness  Cause degranulation of mast cells and Basophils  The Major basic protein blocks muscarinic receptor 2 leading to increase Acetylcholine thereby increasing airway hyperresponse.

6. Mast Cell  Derived from CD 34 progenitor cells in the marrow.  Upon entering the circulation they migrate to the peripheral tissues where they mature and STAY.  Unlike mature Eosinophils and Basophils, mature mast cells do not circulate in Blood.  These lie amongst Epithelial cells of Organs exposed to the environment  Preformed mediators e.g.: Histamine, Serine proteases, and proteoglycans are released on degranulation  The most important mast cell derived lipid mediators act on the Arachidonic acid pathway ( Cyclooxygenase and Lipooxygenase causing inflammation.

lGenetic predisposition lEnvironment changes lDecreased exposure to infectious micro-organisms and/or changed commensal flora – the hygiene hypothesis lEvolution of the “western lifestyle” What are the causes?

TH0TH0 TH1TH1 TH2TH2 Interferon  Interleukin 2 Cell-mediated Immunity Interleukin 2 Interleukin 5 Interleukin 13 Allergic Disease Humoral Immunity Intracellular Pathogens Interleukin 12 Allergens Interleukin 4 JAMA. 1997;278:1845.

Phase 2 – Clinical Disease Adapted from Naclerio. N Engl J Med. 1991;325: Early Phase Late Phase Allergen IgE antibodies Resolution Complications Cellular Infiltration Glands Nerves Blood vessels Sneezing Itching Rhinorrhea Congestion Mediator release Eosinophils Basophils Monocytes Lymphocytes Mast cell Irreversible Disease? Priming Hyper- responsiveness Late-phase reaction

Overview of the Allergic Inflammatory Cascade in Patients with IgE-mediated Asthma Release of IgE Plasma cell B lymphocyte  -switch Allergic Exacerbation Allergic Inflammation: eosinophils and lymphocytes Allergens Mast cells Basophils Allergic mediators

IgE-dependent Release of Inflammatory Mediators IgE Allergens Fc  RI Over Minutes Lipid mediators: Prostaglandins Leukotrienes Wheezing Bronchoconstriction Over Hours Cytokine production: Specifically IL-4, IL-13 Mucus production Eosinophil recruitment Immediate Release Granule contents: Histamine, TNF- , Proteases, Heparin Sneezing Nasal congestion Itchy, runny nose Watery eyes

MECHANISMS OF ALLERGY- Th2 Antihistamines work well in Allergic Rhinitis yet they are relatively contraindicated in Asthma where they do not seem to work ? Ipratropium is indicated in Asthma but not in Eczema or Allergic Rhinitis ? 3 Phases Early Phase Response Late Phase response Chronic allergy disease

EARLY PHASE RESPONSE starts 0-10 minutes and subsides in 1-3 hours Immediate response caused by Mast cell degranulation which produces Itching, sneezing, wheezing, abdominal cramps etc depending on target organ. Increased vascular permeability..tissue swelling and shock.

LATE PHASE RESPONSE Starts within hours and lasts 24 hrs Maximizes around 6 hours producing SKIN- oedema, redness, swelling, itching NOSE- Blockage LUNG- Wheeze An infiltrate of Th-2 cells causing release of TNF and Adhesion molecule causing apoptosis and increased infiltration on Eosinophils

CHRONIC ALLERGIC DISEASE  Tissue inflammation lasting days to years.  IL3 and IL5 causing delayed apoptosis of cells and self generation of Eosinophil.  Tissue remodeling leads to irreversible changes in target organs.  Asthma: Thickening of airway wall, Increased submucosal tissue, and smooth muscle hypertrophy and hyperplasia causing a permanent impairment in Lung Function Test.  Skin: Lichenification  Nose : Initial hypertrophy and polyps, later atrophy

Definition of Anaphylaxis Systemic allergic reaction –Multiple organ systems may be involved Acute onset IgE mediated Manifestations vary from mild to fatal May be uni-phasic, biphasic (30-40%), or prolonged (rare)

Features 1 Def: An altered state of reactivity to Environmental antigen. Most allergy have target organs that are open directly to the environment Gastrointestinal Respiratory ( Including Eye, Nose, Sinuses ) Skin

Features-2 A family disposition in >50% showing Dendritic cell surface marker D2. These act via Th2 cells of Mast cell, eosinophil and Basophilic origin leading to a production of IgE antibodies. A proliferation of new antigens, coupled with global warming, Lifestyle changes, pollution etc has shown a dramatic increase in allergies. Tracheal Dendritic Cells

Genetics  Strong Familial disposition  50% if one parent affected  66% if both parents affected  60% heritability in twin studies  5q code for IL3,4,5,9,13 and GM-CSF resulting from a Cytosine to Thymidine change at position 589 of the IL4 promotor region.  11q13 codes for the IgE receptor Fc epsilon R1 Beta  SPINK-5 gene coding for serine protease mutation causes Nethertons disease –Severe Eczema, asthma and eosinophilia

HISTORY TAKING.1 All symptoms with time line and progression Recurrent and reversible Exposure to common allergens eg.Carpets, moulds, curtains, pollen and nuts etc. Response to previous therapy More than one organ system involved in 80%

HISTORY- 2 Certain characteristic behaviors associated Allergic Salute (Nasal crease) Repeated sneezing Rubbing of eyes Rapid blinking of eyelids Allergic Cluck (Palatal itch) ADHD and irritability Glue ears ( Inattention )

HISTORY..3 During acute episodes look for aggravation factors. Viral infection Pets and animal contact Smoke exposure, high humidity Mites, Moulds, cockroach's Nuts, cheese, banana, eggs, foods etc

History-4 Age is important in both causation and presentation. Infants and young children are first sensitized to Perennial allergens e.g. dust mite, animal dander and fungi. Relevant sensitization to seasonal aerogens takes several years. Food Allergies- more common in infants and young children– GI and skin. If lungs think super infection with RSV, CMV, Herpes, Cytoplasma etc, attaches to the basilar layer of epithelium and triggers Th2 response. Infants seborrhoeic dermatitis, converts to flexural eczema ( Darriers disease), in toddlers and converts to Extensor eczema later !

PHYSICAL EXAM- 1 PEFR or Spirometry should be performed to confirm diagnosis of Asthma and to follow up useful in age 5 and above. (reversibility demonstrated) If respiratory distress –Pulse Oximetry. All. Rhinoconjunctivitis observe for mouth breathing, cheilitis, sneezing, sniffing, runny nose and eyes Higher incidence of atopy with cradle cap Age 4 and above, counting upto 20 in a single breath gives a gross value of lung function In Infants and toddlers flexural and facial eczema later converts to extensor eczema of knees and elbows

Physical Exam 2: Allergies present a dynamic spectrum of Asthma, Eczema and hay fever witch appears to wax and wane. Allergy to something as common as cow milk can mimic Coeliac disease, GERD, Severe Iron deficiency, and chronic diarrhea. 30% of Cow milk allergies are also allergic to soy protein History of recurrent pneumonia suggests Asthma Pulsus Paradoxus Glue ear, Polyps nasal, Pale boggy mucosa with stringy discharge Skin Xerosis

Physical Exam: 3 Lower eyelid puffiness and blueness (Allergic shiners) Dennie Morgan folds. Subconjunctival hgg suggests bronchiolitis or pertussis Improvement with bronchodilators suggests Asthma Fever and purulent discharge not a feature Improvement with position suggests GERD

Physical Exam :4 Adenoidal hypertrophy, Tonsillar Hypertrophy Post nasal drip Snoring OSAS Pharyngeal submucus lymphoid hypertrophy cobblestoning

DIAGNOSTIC TESTING Blood, Nasal secretion, Bronchial eosinophilia RAST 1. SpirometrySpirometry 2. Allergy TestAllergy Test 3. Histamine Challenge TestHistamine Challenge Test 4. BronchoscopyBronchoscopy 5. Sleep LabSleep Lab 6. Environment Pollen Counter End Tidal CO Test Biopsy Environment Pollen CounterEnd Tidal CO Test Biopsy 7. Exercise Induced bronchoconstriction FEV1 <12%

Allergic rhinitis and conjunctivitis This can be atopic (associated with IgE antibodies )or non-atopic. It is an underestimated cause of childhood morbidity. The disease can be classified as intermittent or persistent and mild or severe, although in temperate climates it is often classified as seasonal (related to seasonal grass, weed or tree pollens) and perennial (related to perennial allergens such as house-dust mite and pets). It affects up to 20% of children and can severely disrupt their lives. In addition to its classic presentation of coryza and conjunctivitis, it can also present as ‘cough variant rhinitis’ due to a post-nasal drip, and as a chronically blocked nose causing sleep disturbance and impaired daytime behavior and concentration, or with predominant eye symptoms. It is associated with eczema, sinusitis and adenoidal hypertrophy and is closely associated with asthma. Treatment of allergic rhinitis may improve the control of coexistent asthma

Asthma Asthma is the most common chronic respiratory disorder in childhood, affecting 15–20% of children. Worldwide there has been a significant increase in the incidence of asthma over the last 40 years, although this has now plateaued in many developed countries. Although the symptoms of asthma are readily controlled in most children, it is an important cause of absence from school, restricted activity and anxiety for the child and family. There are still about 20 deaths from asthma children each year in the UK. Diagnosing asthma in preschool children is often difficult. Approximately half of all children wheeze at some time during the first 3 years of life. In general, there are two patterns of wheezing Transient early wheezing Persistent and recurrent wheezing.

Asthma Transient early wheezing Most wheezy preschool children have virus-associated wheeze (also known as episodic viral wheeze and wheezy bronchitis). Transient early wheezing is thought to result from small airways being more likely to narrow and obstruct due to inflammation and aberrant immune responses to viral infection. This gives the condition its episodic nature, being triggered by viruses that cause the common cold. Studies have found that transient early wheezers often have decreased lung function from birth, from small airway diameter. Risk factors include maternal smoking during and/or after pregnancy and prematurity. A family history of asthma or allergy is not a risk factor. Transient early wheezing is more common in males and usually resolves by 5 years of age, presumably from the increase in airway size.

Asthma Transient early wheezing Atopic asthma (IgE-mediated) Non-atopic asthma Recurrent aspiration of feeds Inhaled foreign body Cystic fibrosis Recurrent anaphylaxis in a child with food allergies Congenital abnormality of lung, airway or heart Idiopathic.

Asthma Persistent and recurrent wheezing Some children, both preschool and school-aged, have frequent wheeze triggered by many stimuli. The presence of IgE to common inhalant allergens, such as house dust mite, pollens or pets, is associated with persistence of wheezing beyond the preschool years. Recurrent wheezing associated with evidence of allergy to one or more inhaled allergens (e.g. by skin-prick test or IgE blood test) is termed ‘atopic asthma’. Atopic wheezers have persistent symptoms and decreased lung function. Atopic asthma is strongly associated with other atopic diseases such as eczema, rhinoconjunctivitis and food allergy, and is more common in those with a family history of such diseases

Asthma Medications:1 Anti-inflammatory medications are most commonly needed. 1. Inhaled corticosteroids (ICS) 2. Leukotriene Montelukast (Singulair) 4. Short acting B-agonists (SABA) Albuterol 5. Long acting B-agonists (LABA) Salmeterol (Serevent) Fomoterol (Foradil) 6. Combination ICS/LABA

Asthma Medications:2 7. Theophylline 8. Oral corticosteroids 9. Anti-lgE antibody Omalizumab (Xolair) Plavizumab 10. Occasionally other immune inhibitors Methotrexate Cyclosporin

Urticaria and angioedema Acute urticaria usually results from exposure to an allergen or a viral infection, which triggers an urticarial skin reaction. It may also involve deeper tissues to produce swelling of the lips and soft tissues around the eyes (angioedema), and even anaphylaxis. Chronic urticaria (persisting >6 weeks) is usually non-allergic in origin. It results from a local increase in the permeability of capillaries and venules. These changes are dependent on activation of skin mast cells, which contain a range of mediators including histamine.. Treatment is with second-generation non-sedating antihistamine

Eczema Eczema is classified as atopic (where there is evidence of IgE antibodies to common allergens) or non-atopic.Atopic eczema is classified as an allergic disease as many affected children will have a family history of allergy, at least 50% develop other allergic diseases and IgE antibodies to common allergens are present. There is a close relationship between eczema and food allergy, particularly in young infants with severe disease; up to 40% of them have an IgE-mediated food allergy, in particular egg allergy. Screening by skin prick or IgE blood testing should be considered

Contact dermatitis

Food Allergy Food Allergy Affects up to 6% of children The most common causes are milk, egg, nuts, seafood, wheat, legumes, seeds and fruits Diagnosis of IgE-mediated food allergy is based on a suggestive history supported by skin-prick tests or specific IgE antibodies in blood Supervised food challenge is sometimes necessary to clarify the diagnosis Those at risk of a severe reaction, e.g. with coexistent asthma, should carry an epinephrine (adrenaline) auto-injector.

Common Allergens 66 © 2010 Children’s Memorial Hospital Soy Cow’s milkPeanutTree nuts FishShellfish Egg white Wheat

Drug allergy Drug allergies do occur in children, especially to antibiotics, but only a minority who are labeled ‘drug allergic’ are truly allergic. This is usually because viral illnesses, for which children are often Prescribed antibiotics, themselves cause skin rashes. A detailed history is required of the nature and timing of the rash in relation to taking the antibiotics. Allergy skin and blood tests can be used to support a diagnosis of drug allergy, but a drug challenge may be the only way to conclusively confirm or refute the diagnosis. This is contraindicated after a severe allergic reaction and an alternative drug should be sought

SEASONAL AEROALLERGENS Certain aeroallergens change with seasons temperature, and Geographic locations. Cold dry air can sometimes incite allergy. Hot humid air, dust mite allergy Wild plants in India esp., Wild grass, Devils tree, Litchi and Mango pollen Trees pollinate – March to July Grasses pollinate – July to October Weeds pollinate – October- March

PERRENIAL (YEAR –ROUND ) Once sensitive also to seasonal baseline and worsening in March - April and Sept -Oct Dust mites Animal Dander Cockroach- Inner city Fungi Aspergillus, Pennicilinum,-- Indoor Alternaria– both Indoor and Indoor

Allergy Prevention Strategies Promote breast feeding Discourage early introduction of solid and “at risk” food (milk, eggs, peanuts, seafood, ? meats) Reduce dust mite levels in homes Avoid exposure to animal dander Screen for allergy at all routine exams Encourage awareness of allergen control measures at work, school, and daycare

Conclusion Atopy – propensity to produce high levels of IgE from B cells Allergens mimic parasites – processed and presented by APC (e.g. dendritic cells) Orchestrated by Th2 cells – cytokine release Effector cells – mast cells, basophils Mediators – cytokines, histamine, leukotrienes, PAF etc.