Pediatric Urticaria Urticaria & Angioedema:

 A reaction that A Practical Guide causes raised, red, itchy welts in sizes ranging from small spots to large blotches several inches in Mark E. Bubak, M.D. diameter. Individual Allergist, Dakota Allergy & welts appear and fade as the reaction runs its Assistant Professor, Sanford School of course. This is typically Medicine—Internal Medicine & Pediatrics less then 24 hour lesions.

Urticarial Classification Angioedema

 Acute: Less than 6 weeks duration  A related type of  Chronic: More than 6 weeks duration swelling that affects deeper layers in the skin, often around  How long does the hive remain? eyes and lips. Many ’  Any other symptoms or signs with the types don t itch. Duration is longer-1 ? or 2 days.

Mast Cells & Basophils Mast Cells Mast Cell Activation/Degranulation IgE Immediate

 IgE Immediate Hypersensitivity  Causes

 Classical Complement Pathway  ALLERGENS  Modified IgE; IgG, Autoimmune anti-IgE or  Alternative Complement Pathway FcɛRI; or FcɛRII (CD23) on platelets or  Direct Activation of Mast Cell or .

 Plasma-kinin Generating System  Mediators

 Histamine, leukotrienes PGD2, PAF, ECF- A, HRF

Activation of Classical Complement Activation of Alternative Complement Pathway Pathway

 Causes:  Causes:

 Antigen-antibody complexes  IgA-antigen complexes, complex

 IgM, IgG1, IgG2, or IgG3 polysaccharides, lipopolysaccharides

 Mediators:  Mediators:

 C3a, C4a, C5a (anaphylatoxins) cause  C3a, C4a, C5a (anaphylatoxins) cause release of mast cell mediators release of mast cell mediators

Direct Activation of Mast Cell Membrane Plasma-Kinin Generating System

 Causes:

 Morphine, Codeine, Polymyxin Antibiotics, Thiamine, Radiocontrast Media, Vancomycin, Certain Foods--strawberries

 Mediators:

 Opiates act through specific receptors to release histamine

 Others nonspecifically activate cell membrane to release or generate mast cell mediators Plasma-Kinin Generating System

 Causes:

 Activation by Negatively charged surfaces, collagen vascular basement membrane, or endotoxin.

 Mediators:

 Bradykinin; thrombin activation; especially for HAE & some CIU

The Urticarial Spectrum IgE Mediated Episodic Hives

 Acute Reactions—Often in minutes or hours  IgE Mediated Episodic Hives  Very common---Normally with other  Acute Consistent Urticaria Symptoms

 Physical Urticarias  Common With Foods—Within 2 hours

 Nuts, Shellfish, kiwi, egg white, milk, soy, etc.  Contact Urticaria--dog lick, laying in ragweed  Chronic Idiopathic Urticaria  Hymenoptra--often with anaphylaxis

 Exercise plus specific food combination

IgE Mediated Episodic Hives IgE Mediated Episodic Hives Evaluation: Therapy:

 HISTORY!!!  Avoidance

 Prick Skin Tests or ImmunoCaps help  Antihistamines--remember they take 30 confirm cause and effect minutes to work.

 Exam: The lesions don’t bruise, last  No effective/safe immunotherapy less than 24 hours and can have itchy available for food allergy.

angioedema as well.  If part of anaphylaxis: Epinephrine! IgE mediated urticaria is most IgE mediated urticaria is most often caused by: often caused by:

 A) Peanuts  A) Peanuts

 B) Ragweed  B) Ragweed

 C) Dust Mites  C) Dust Mites

 D) ASA  D) ASA

Ashley Ashley

 Ashley receives her allergy shot after school  Diagnosis: and has a granola bar and apple juice in your waiting room during her observation 30 minute wait. At 20 minutes she is at the nurses window complaining of itchy face, chest and legs.

 Many wheal and flare lesions are noted in those areas.

Ashley Ashley

  Diagnosis: Allergic reaction from Diagnosis: Allergic reaction from allergy allergy shot shot (Keep food allergy in mind, too)

 Evaluation/Treatment: Epinephrine  Evaluation/Treatment: 1:1,000 IM, then antihistamine, dose and closely observe and treat as needed. Allergist gets notified later and next steps agreed upon. Acute Consistent Urticaria

 Daily Hives--Aggressive, Waves of Hives 

 Viral, Strep  Drug Reactions  (Think Serum Sickness Mechanism)  Generally Not IgE  Often Lasts 1 or 2 Weeks

Acute Consistent Urticaria Acute Consistent Urticaria Evaluation: Therapy

 HISTORY and EXAM  Remove offending drug

 Rapid strep/culture  Treat  Comfort:  LFTs, Hepatitis Serology  Itch control: Antihistamines, Steroids  Drug Allergy Testing (only PCN)  Explain what is happening and that it will  4+ Weeks Later pass. Many patients fear hives will go to  Avoiding most allergy testing!! anaphylaxis and death.  Try not to do harm!

Accurate allergy testing is available for: Accurate allergy testing is available for:

 A) Sulfa  A) Sulfa

 B) Penicillin/Amoxicillin  B) Penicillin/Amoxicillin

 C) Cephalexin  C) Cephalexin

 D) Azithromycin  D) Azithromycin

Physical Urticaria Urticaria

 Chronic, with problems often for years  Dermatographic  Onset In Minutes  Heat--Cholinergic--small lesions  Short Duration  Cold (+/- anaphylactic)  Vibration

 Pressure (dermatographism vs.  Delayed Pressure delayed)  Onset 30-60 Minutes  Longer Duration  Aquagenic

Physical Urticaria Ice Cube Test Evaluation & Treatment:

 Challenge helps confirm but HISTORY is key.  Heat, scratching, some meds worsen all types  Avoidance is the main therapy  Daily antihistamines  At times more Rx is needed, but be cautious of side effects in the long term.  These conditions often go on for years.

Angioedema

 Non-itchy swellings--’deeper’ hives

 BRADYKININ, prostaglandins, leukotrienes, seratonin, etc. play a big role

 Usually have longer duration lesions

 Often found with hives--similar cause in those cases Angioedema Hereditary Angioedema

 For Non-Itchy Think:  C1 Esterace Inhibitor ‘Deficiency’  Type I: Low Amount  ACE Inhibitors  Type II: Non-functioning protein  Familial Hereditary Angioedema  Type III: Unknown, female only, nl C4 (very rare)  Acquired Angioedema  Autosomal Dominant  Idiopathic Angioedema  But plenty of spontaneous mutations, too  1 in 100,000 population  Typical onset as kid  Not uncommon--GI, GU, airway, and post- traumatic symptoms

Hereditary Angioedema Hereditary Angioedema Diagnosis Therapy

 Screen: C4  ABCs, Pain Control, Fluids with attacks

 Actual:  Replace C1 Esterace Inhibitor  Prevention (Cinryze)  C1 Esterace Inhibitor level quantitative  Attacks (Berinert, Ruconest)  C1 Esterace Inhibitor level functional  Danazol, Stanazolol, Aminocaproic Acid  With Attack:  Bradykinin Inhibitor (Firazyr)  C2 is low or absent (types I & II)  Kallikrein Inhibitor (Kalbitor)

A low C4 level is found in asymptomatic Acquired Angioedema patients with:

 Type I (AAE-1): With other disorders, often  A) Peanut Allergy has hives, at times . Serum  B) ACE inhibitor angioedema sickness/ mechanism. Low C1q, C1-INH, C4, no FH.  C) Hereditary Angioedema

 B Cell Lymphoproliferative Disorders  D) Allergic Asthma  Type II (AAE-2): Auto-antibodies to the C1 Esterase Inhibitor. More common. Not associated with malignancy. Low C1q, C1- INH, C4, no FH. The non-itchy swelling of angioedema A low C4 level is found in asymptomatic predominantly depends upon which patients with: substance?

 A) Peanut Allergy  A) Histamine

 B) ACE inhibitor angioedema  B) Bradykinin

 C) Hereditary Angioedema  C) Tryptase

 D) Allergic Asthma  D) IgG

The non-itchy swelling of angioedema predominantly depends upon which substance?

 A) Histamine

 B) Bradykinin

 C) Tryptase

 D) IgG

Urticarial Vasculitis Urticarial Vasculitis Clinical Presentation

 Chronic Eruptions of erythematous wheals that  Urticarial Eruptions

resemble urticaria but histologically show  Often burning or painful sensation rather changes of small vessel leukocytoclastic than itch vasculitis.  Duration over 24 hours  Type III Hypersensitivity Reaction  Petechiae, ecchymoses,  Ag-Ab complexes deposited in vascular lumina--complement activation & chemotaxis postinflammatory of  Angioedema of face or hands  Very Rare In Pediatrics  ??About 2% of Chronic Urticaria Urticarial Vasculitis Urticarial Vasculitis Clinical Presentation: Non-dermal Associated Conditions & Ddx

 Most Are Idiopathic  Non-Dermal  Collagen

or associated with onset of  esp.

urticaria, Lymphadenopathy (40%)  Also Sjogren Syndrome, Monoclonal Gammopathies, Mixed Cryoglobulins, hematologic  Obstructive Disease (21%) & solid malignancies  Abdominal or Chest Pain (17%)  Viral Infections  Photosensitivity  i.e. Hepatitis B, C; Mononucleosis

(10%)  Serum Sickness   Raynaud’s Phenomenon (6%) Drugs:  ACE Inhibitors, PCN, Sulfas, Fluoxetine, cimetidine,  Episcleritis or (4%) diltiazem, thiazides, potassium iodide, NSAIDs, glatiramer acetate.

Urticarial Vasculitis Urticarial Vasculitis Clinical Laboratory Tests A Subset of Vasculitis

 CH50, C3, C4, C1q--Decreased in 1/3  Clinically  Associated with purpuric resolution, sxs of , , and obstructive lung  Urticarial Skin Lesions disease  Histologically--  Associated with histologic findings--interstitial neutrophilic infiltrated of the & IF of Igs or  Necrotizing Vasculitis C3 deposited in the blood vessels & along the basement membrane zone  Antibodies to C1q  Other labs as indicated clinically

 CXR, UA, PFT, Hepatitis studies, ANA, etc.

Urticarial Vasculitis Urticarial Vasculitis Therapy Conclusions

 NSAID--Indomethacin (Indocin)  A Part Of The Urticaria Spectrum  Antihistamines  Hives That Last > 24 Hours, Leave  Oral Steroids  Antimalarial-hydroxychloroquine(Plaquenil) Bruise, That Burn Or Are Painful   Association With Arthralgia, Arthritis,  Systemic Symptoms In Some Patients  Cyclosporine  Dapsone  Important  Effective Therapy Is Available Chronic Idiopathic Urticaria

 Over 6 Weeks Of Hives

 Lymphocytic, Neutrophilic, Mixed

 Unknown significance

 Biopsy Without Vasculitis

 Dx When Everything Else Is Ruled Out

 Very Frustrating

Chronic Idiopathic Urticaria Chronic Idiopathic Urticaria Evaluation

 HISTORY and PHYSICAL  Possible Mechanisms  A very frank discussion with the patient (and family if  Autoimmune needed) about yield of tests.

 Anti-IgE  97%+ are “Normal”

 Interleukins (IL-1, 3, 5)  Can include evaluation (colon, , hematologic, lung), special diets without dyes or  HRF (histamine releasing factor) preservatives, hepatitis serology, chemistries, CBC,  Neuroimmunological Tryptase, SPEP, thyroid function and antibodies, (ANA, RF, etc.), parasites, ETC.

 Allergy testing normally only gives some objective evidence that allergy isn’t involved.

Chronic Idiopathic Urticaria Evaluation FcεRI

 Antibody against the mast cell receptor  FcεRI: High-affinity receptor for IgE for IgE (FCER1) (30-40%)  Antibody against IgE (5-10%)  Antibody against low affinity mast cell receptor for IgE (FCERII)

Functional autoantibodies of CIU. IgG–anti-IgE antibodies combine with and cross-link adjacent receptor-bound IgE. IgG–anti-FcεRI antibodies combine with and crosslink adjacent α-chains of FcεRI. Black notched membrane structures represent α-chain of FcεRI expressed on the surface of a dermal mast cell.

Chronic Idiopathic Urticaria Clinical diagnosis Evaluation

 Currently the clinical diagnosis depends  So What Do We Do??? on autologous serum skin testing.  H & P  Basic Labs-try not to miss cures/major issues

 CBC with diff Autologous serum-plasma skin test. PBS, Saline solution negative control; serum and plasma  Sed Rate are injected in a volume of 0.05 mL and the  Metabolic panel

reaction read at 30 minutes. Both serum and  Autoimmune plasma have given positive responses. The  Diet Trials (or some allergy reaction at the injected site is examined 30 testing) minutes later. A wheal with a diameter at least 1.5 mm greater than a control saline solution  Remove Medications wheal is deemed positive

Chronic Idiopathic Urticaria Chronic Idiopathic Urticaria Treatment Treatment

 Education: Average duration 2+ years  Nonspecific Factor Avoidances If (14% > 5 yrs), non-fatal disease, not Applicable

food or drug related, etc.  Fever, illness  Comfort: Daily non-sedating  Heat, exercise antihistamines, etc.  Alcohol ingestion  DO NO HARM!  Emotional Stress  Menstrual Cycle, hyperthyroidism  Consider ‘anti-inflammatories’  ASA

Chronic Idiopathic Urticaria Treatment: Antihistamines Jennifer

 Comfort: Daily non-sedating  Jennifer is a 17 year old with 2 years of hives.  OK to push the dose: 2-4 times allergic rhinitis dosing

 Loratadine

 If still symptoms--add an older, 1st generation bruise, hit anywhere and anytime. Despite

 Hydroxyzine, Doxepin, Chlortrimeton zyrtec twice daily, zantac, and singulair she  These do effect performance often has to cancel events with family and  Try adding H2 blockers and leukotriene blockers friends due to the hives and can’t sleep well.  DO NO HARM! She is tired and frustrated. Otherwise, she is healthy.

** Response Rate 45% of Patients (Kaplan 2014) Chronic Idiopathic Urticaria Chronic Idiopathic Urticaria Treatment Treatment: Xolair (omalizumab)

 Anti-inflammatories--Think as a  Monoclonal Anti-IgE (human & murine) Rheumatologist  65% of refractory patients respond well  Omalizumab (Xolair)  35% are hive free  Cyclosporine  Onset in days. Very well tolerated!  Dapsone  150 or 300 mg every 4 weeks. No need to  colchicine, hydroxychloroquine, tricyclic antidepressants, SSRIs, plasmaphoresis, get an IgE level for dosing. stanozolol, indocin  Rare anaphylaxis, question of coronary issues, with main side effect being cost.

Chronic Idiopathic Urticaria Chronic Idiopathic Urticaria Treatment: Cyclosporine Treatment: Dapsone

 Immunosuppressive  About 2/3rds respond  Also inhibits histamine release from human basophils and skin mast cells  For , anti-inflammatory

 60 to 80% response rate in CIU patients  Be sure they have G6PD failing high dose H1 blockade  Follow Hg, liver function, fatigue  Help starts within a week  Find lowest effective dose  Toxicity issues: , Decrease Renal Function

Chronic Idiopathic Urticaria Jennifer Treatment

 This is long term treatment!   Recheck periodically We added Xolair 300 mg every 4 weeks

 When better, cut back on meds starting  Better at day 3 with most toxic one  No hives after 2 weeks  May need to increase Rx during illnesses  Likely try the 150 mg dose in future  Keep vigilant for other issues  25% have thyroid antibodies  After disease ‘Quits’, it recurs in 1/3 Antibody mediated autoimmune chronic Antibody mediated autoimmune chronic urticaria can be caused by all of the urticaria can be caused by all of the following except: following except:

 A) Antibody against the high affinity  A) Antibody against the high affinity mast cell receptor for IgE (FCER1) mast cell receptor for IgE (FCER1)

 B) Antibody against IgE  B) Antibody against IgE

 C) Antibody against low affinity mast  C) Antibody against low affinity mast cell receptor for IgE (FCERII) cell receptor for IgE (FCERII)

 D) Antibody against condrointin  D) Antibody against condrointin

Hives Hives Conclusions Conclusions

 Recognize The Spectrum  Testing For IgE In Specific Types Only  Acute IgE Reactions  Seek Underlying Cause & Correct  Acute Consistent If Possible  Physical  Control Symptoms  Urticarial Vasculitis  DO NO HARM!

 Chronic “Idiopathic”

Thank You Questions?