Non-respiratory allergic disordersNon-respiratory allergic disorders

Prof. Dr. Dieter Koller

Core Unit - Paediatric Ambulatory Care

University Children‘ s Hospital Vienna, Austria

Which symptoms

may lead to the assumption of an allergic disordermay lead to the assumption of an allergic disorder

Itching Rash urticaria

diarrhea abdominal pain vomiting

Wheezing Coughing Breathlessness Sneezing/Rhinitis Conjunctivitis

Diagnostic armatorium

• PATIENT´S HISTORY• SKIN TESTING (PRICK, PRICK to PRICK, PATCH,

SCRATCH, INTRADERMAL)• SEROLOGICAL IGE DETERMINATION• PROVOCATIONTESTS

– Nasal– Conjunctival– Bronchial– Insects– Food (DBPCFC)– drugs

Patient´s history

• Which symptoms?

• When/Since when?

• How long?

• How frequent?

• Where?

• Any medication until now – any success?

PRICK-TESTING

PRICK-TESTING

Male, 5 a, hayfever symptoms since 2 years, from end of may to the middle of june

When is skin prick testing not useful?

• Medication: e.g. antihistamines, steroids, immunosuppression

• diseases: e.g. Mastocytosis, atopic eczema, urticaria

• Testing of many allergens

When is a skin prick test positive?

The size of the wheal decides whether a test is positive or negative:

• Negative = no wheal reaction, reaction same as the negative control (normal saline)

• Indifferent but not positive = small wheal reaction less then 2mm

• positive = Wheal reaction at least of 3 mm and at least the same diameter as the positive control

• Documentation by copying the wheal size

Serological Allergy Testing

• Determination of serum IgE (total and specific IgE)

• More then 700 allergens can be tested

• Measurement of specific IgG-Ab do not contribute to the diagnosis of type I hypersensitivities

TREATMENT OF ALLERGY

• ALLERGEN AVOIDENCE

• SYMPTOMATIC TREATMENT (antihistamines, steroids,…)

• CAUSAL TREATMENT (SCIT)

It was just an insect sting

Insect sting/venom allergy

• Raised local reactions may occur in 19% of all humans

• Systemic reactions in 0,8–5% of all humans

• Positive skin test reactions or specific serum-IgE-Ab against bee or wasp venom in up to 25% of all humans

• There exists no relationship between atopy and hymenoptera-allergy

In China there is high prevalence of increased serum IgE-Ab against bee venom

Patient´s history

classification of field sting reaction:

• – Time interval between sting and any reactions?

• – Symptoms? – Severity?

• – Therapy?

DIAGNOSTICS

SKIN PRICK-TESTING• Prick testing with increasing hymenoptera

venom concentrations (0,1 – 1 – 10 – 100µg/ml). Documentation of each reaction after 15 min, if any local wheal reaction occurs testing ends.

IgE-Measurement• Specific serum-IgE-Ab against insect venom

Sting challenge

Bee/Wasp sting challenges

1.) reported severe anaphylactic reactions after field sting but negative SPT and negative IgE-Ab 2.) Follow-up/before termination of SCIT 3.) before starting immunotherapy when patient’s history is not clear

only 28% of patients with a history of Hymenoptera anaphylaxis developed an anaphylactic reaction after an in-hospital challenge (vd Linden, et al. JACI 1992)

TREATMENT

• SCIT: if anaphylaxis grade (II), III and IV occurred after field sting

• Symptomatic treatment after anaphylaxis grade I and II

Patient 1: boy 8 yrs, bee sting 1 week ago, urticaria, no other symptoms

IgE-Measurement• Bee – class 1• Wasp - class 0• Total-IgE 23kU/L

Interpretation: cutaneous bee venom sensitization,

Follow-up of IgE after 3 weeks : Bee – class 6

Patient 2: boy 7 yrs, insect sting for 3 weeks, urticaria, shortness of breath, laryngeal edema, hypotension

IgE-Measurement

• Bee – class 4

• Wasp- class 5

• Total-IgE 56 kU/L

Interpretation: Sensitization against bee and wasp venom

Further IgE-determination after 6 weeks: bee – class 5

wasp – class 2

Alternative: Component diagnostics

Therapy: SCIT with bee venom

ANAPHYLAXIS

• Anaphylaxis is the most severe allergic reaction and is life-threatening.

• Even very small amount of an allergen is needed for most severe reaction.

• Anaphylaxis is an extreme case of emergency and needs immediate treatment.!

• Fatalities in children are rare

Triggers of anaphylaxis

• Food (nuts, cow‘s milk, (shell)fish, egg)

• Insect venom

• drugs

• unknown (exercise,..)

Signs of an imminent anaphylaxis

• itching and or burning sensations in the throat

• Pruritus, Flush

• Quincke-edema

• nausea, abdominal cramps, vomiting

• general anxiety, dizziness, adynamia

Differential diagnosis of ANAPHYLAXIS

• Cardivascular disorder syncope arrhythmias

• Endokrinologic disordershypoglycemia

• Neurological/psychiatric disorders hyperventilation panic attack seizures metabolic coma

• Respiratory disorders Tracheal/bronchial obstruction (e.g. foreign body) Asthma attack

• Pharmakologic-toxic Effects Intoxikation

Severity of anaphylaxis (Ring et al.)

Grade skin abdominal respiration circulation

I Itching

Flush

Urticaria

Angioedema

II Itching

Flush

Urticaria

Angioedema

Nausea

cramps

Rhinorrhoea

hoarseness

Dyspnea

Tachykardia

Hypotension

Arrhythmia

III Itching

Flush

Urticaria

Angio-edema

vomiting

Defecation

laryngeal edema

bronchospasm

cyanosis

Shock

IV Itching

Flush

Urticaria

Angio-edema

vomiting

Defecation

respiratory arrest cardiac arrest

Patient with anaphylactic reaction

Severity IV

Basic management, fluid

Severity III

Severity II

Severity I

Resuscitation, Adrenalin i.m., i.v. line, Adrenalin i.v., fluid,(antihistamines i.v.), steroids i.v.,

Intensive care unit

Adrenalin i.m., fluid, perhaps adrenalin i.v., oxygen, antihistamines i.v.

Predominantly cardivascular

Adrenalin i.m. Fluidsteroids i.v.OxygenAntihistamines i.v.

Predominantly respiratory

Antihistamines H1 i.v.steroids i.v.Observation for at least 4 hours

Adrenalin inh. perhaps i.m.Beta2-Agonists inh.antihistamines i.v., steroids i.v., perhaps beta2-agonists i.v., oxygen

Admission and observation

yes

yes

yes

yesyes

yes

yes

no

no

no

THERAPY – specific measures

VOLUME

ADRENALINE

Antihistamines i.v./p.o. ?

Steroids i.v./p.o.?

Beta2-Agonists topically ?

Beta2-Agonists i.v. ?

For prevention of further anaphylactic reactions

1.) Epipen auto-injector junior. (<30 kg), Epipen auto-injector (>30 kg)

2.) steroids p.o.

3.) antihistamine p.o.

4.) inh. beta2-Agonists

Drug Allergy

Type Symptoms Example

I (IgE) anaphylaxis Penicilline

II (zytotoxic) agranulocytosis, hemolysis, thrombopenia

Penicilline, Carbamazepine, Metamizol, Cephalosporines

III (Immune complex)

serum-disease, vasculitis, alveolitis

Serum, Dextrane, Penicilline, Phenylbutazone

IV (cellular) Eczema (photoallerg., phototox., hematogen.)

Penicilline, Sulfonamids, Barbiturates, Antibiotics

Mechanisms in Type I allergy and pseudoallergy

allergic pseudoallergic

Type I IgE

(IgG)

Direct release of mediators

Direct complement activation

neuropsychogenic reaction

Local Anesthetics

• Incidence: 2-3% of all applications with local anesthetics results in adverse reactions but in children less then 1% of these are (pseudo)allergic.

• Diagnostic: Skin prick testing is always negative, no in vitro testing

• Provocation testing is the only diagnostic procedure.

Paracetamol

• Incidence: extremely rare in childhood.

• Diagnostik: skin testing ineffective, no in vitro assay

• Only provocation testing

PENICILLIN-G/V

• Incidence:more then 90% of all adverse/allergic reactions in the age of 20 - 49 yrs

Urticaria 4,5% of all treatmentsSystemic reactions 2% of all treatmentsAnaphylactic shock 0,2% of all treatmentsExitus 0,02% of all treatments

• Clinical manifestations: Immediate (< 1 h): Anaphylactic shock, urticaria, Quincke-edema, laryngo- and/or bronchospasmdelayed 1-72 h: Urticaria, pruritus, rash

PENICILLIN-G (-V)

• Immediate(< als 1 h): IgE-Ab mostly against MDMdelayed 1-72 h: IgE-Ab mostly against PPL

• Cross reactivity with cephalosporines 8-10%

• Ampicillin-Rash (5-10 % of all patients treated with aminopenicillin, in EBV-infection up to 90%). Symptoms: erythema und papules. NO ALLERGIC REACTION.

Non-allergic ampicillin reactions

DIAGNOSTICS in PENICILLIN ALLERGY

Skin testing (PRICK, Intradermal) with major component Poly-L-lysine penicilloyl (PPL) and minor determinants (MDM)workflow: PRICK with PPL -> if negative -> intradermal with PPL ->if negative -> PRICKwith MDM -> if negative -> intradermal with MDMWheal 0-3 mm negative

3-5 mm indifferent 5-10 mm positive

>10 mm highly positivefalse negative <1%, false positive <7%

Incidence of positive skin test reactions in all subjects with suspected penicillin allergy is 4.3% but up to 91% in patients with anaphylaxis after penicillin administration.

Unfortunately skin test extracts are not available

since 2 years

IgE-Ab in serumGood correlation with skin prick test results but low

sensitivity

no reliable in vitro or in vivo tests are available, thus provocation tests must be done

Management of PENICILLIN ALLERGY

1.) appropriate diagnosis(provocation)

2.) avoidence or

desensibilisation

0 min 100 U po 2h15min 50000

15 min 200 2h30min 100000

30 min 400 2h45min 200000

45 min 800 3h 400000

1 h 1600 3h15min 200000 U sc

1h15min

3200 3h30min 400000

1h30min

6400 3h45min 800000

1h45min

12800 4h 1000000 im or i.v.

2h 25000

URTICARIA/ANGIO-EDEMA

Causes of UrticariaIMMUNOLOGIC PHYSICAL

a.) IgE-mediated

1.) food

2.) drugs

3.) airo-allergens

4.) insect venom

b.) complement-mediated

1.) transfusions

c.) Systemic disorders

1.) vasculitis

2.) paraneoplastic

1.) dermographism (Urticaria factitia)

2.) Thermic induced urticaria

a.) heat urticaria

b.) cold urticaria

3.) UV-induced urticaria

4.) pressure induced urticaria

5.) aquagenic urticaria

6.) vibratoric urticaria

INFECTIONS HEREDITÄRE DISORDERS

Bacterial, viral, parasitic 1.) Hereditary angioneurotic edema

2.) C1-Deficiency

3.) hereditary cold urticaria

NON-IMMUNOLOGIC FACTORS URTICARIA PIGMENTOSA

alcohol, DAO-deficiency CHRON. IDIOPATHIC URTICARIA

Patient‘s history

• Frequency and duration• Dependent on day-time• Form, size and distribution of wheals• Associated angio-edema• Associated other symptoms• Family history of urticaria or allergies• Current allergies, infections or other diseases• Triggers (food, exercise, cold, heat,...)• Any medication• Any treatment and its response

Diagnostic Procedure in Urticaria

urticaria

< 6 weeks

> 6 weeks Chronic urticaria

Acute urticaria History, clinical diagnosis, treatment

History, dermographism

Infect-triggered urticaria

Allergic urticaria Intolerance triggered urticaria

Physical-induced urticaria

Idiopathic urticaria

Diary for 4- 8 weeks

No evidence

Symptomatic treatment

provocation

Specific IgE

elimination

provocation

Microbiology serology

Specific treatment

Suspected trigger

Oligo-allergenic diet

Oral provocation

Treatment of urticaria

• acute urticaria: antihistamines, (combined with steroids)

• acute urticaria associated with other systemic reactions: see anaphylaxis

• Chronic urticaria: chronic idiopathic urticaria: antihistamines (plus

beta2/Agonists, plus antihistamines H2, steroids are rarely needed) pressure-induced urtikaria: frequently steroids are neededcholinergic Urticaria: antihistamines, (plus danazol, plus

hydroxicine)Urticaria solaris: sun blocker, UV-Radiationcold urticaria: antihistamines, danazol, tolerance induction

Prevalence of food allergy in children with atopic eczema as proven by food challenge

Author year N Allergic %

Sampson 1985 113 56

Burks 1988 46 33

Sampson 1992 320 63

Eigenmann 1998 63 37

Niggemann 1999 107 51

Breuer 2004 64 46

Food Allergy

Specific IgE, skin testing and patient‘s history are rarely related to clinical manifestations

Niggemann et al. 1998: patient‘s history is of low specificity

nutrition/symptoms diary

Diagnostic Procedure in Food AllergyGOLDEN STANDARD

Symptom – Food intake protocol

Patient´s history In vivo-/in vitro testing

Suspected of food allergy

Specific suspected Non-specific suspected

Elimination diet Oligo-allergenic diet

Oral provocation testing (DBPCFC)

Immediate reaction Delayed reaction

Observation 24 h Observation 48 h

positive

Specific elimination

negative

No diet

Proposal for oligo-allergenic diet

cereal: only rice

meat: lamb, turkey

vegetable: cauliflower, broccoli, cucumber

fat: vegetable oil, milk-free margarine

soft drinks: mineral water, tea

spices: salt/sugar

Procedure after unblinding DBPCFC

Verum Placebo Procedure

+ - Elimination diet

+ + Repeat DBPCFC

- + no diet

- - No diet

FOOD ALLERGY

Golden standard of diagnostics is DBPCFC

Recommendations for avoidance of specific food are valid for 12-24 months only. Thereafter food challenges must be repeated.

Any recommendations must be supervised by an experienced dietician.