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Boli Alergice

Aspecte clinice

Diana Deleanu
Boli Alergice

Respiratorii (rinita, astm)

Cutanate (urticaria, angioedema, eczema)

Alergii alimentare (diferite manifestari)

Alergii medicamentoase (diferite manifestari)

Socul anafilactic
Alergii cutanate
• Dermatita atopica – tipul IV Hs
• Dermatita de contact – tipul IV HS
• Urticaria (nivel straturi superficiale) si
angioedemul (la nivelul startului profund al
dermului)– tipul I HS
ACD group 2009,20;149-60
• Alergenii de Contant (contact direct)
• Tipul I HS: urticarie, angioedem
(polen, medicamente etc)

• Tipul IV: dermatita de contact (nichel,


crom, uleiuri de plante etc)
Alergenii cei mai frecvent asociatii cu tipul I HS

Proteine Alimente
 Ser strain  Nucile de copac
Polenul de plante  Fructele de mare

 Iarba (graminee)  Ouale

 Buruieni (ambrozie)  Mazare, Fasole


 Laptele de vaca
 Copaci (mesteacan)

Medicamentele Produsi ai Insectelor


 Venin albina
 Penicilina
 Venin viespe
 Sulfonamidele
 Inhalatori
 Anestezice Locale
 Gindaci de bucatarie
 Salicilatii (aspirina si AINS)
 Acarieni

Spori de mucegaiuri
 Par, piele de animale
Aspecte Clinice ale HS Imediate
Organ Boala Simptome Alergen importanti Calea de
patrundere
Plamin Astm Wheezing, Polen, praf, Inhalare
dispnee, tahipnee animale

Nas si Ochi Rinita, conjunctivita Rinoree, eritem Polen Contact cu


si prurit ocular mucoasele

Piele Eczema (dermatita Prurit, edem, Alimente, Ingestie


atopica) vezicule Medicamente Variate
Urticaria/angiedem

Tract Intestinal Alergie Varsaturi, diaree Alimente Ingestie


gastrointestinala
Sistemic Anafilaxie Soc, Venin Insecte, Intepare
hipotensiune, Medicamente Variate
wheezing (penicilina) Ingestie
Alimente
(arahidele)
“Alimentul pentru un om
poate fi hrana, iar pentru
altul otrava.”
Lucretius
De Rerum Natura
Blockbuster
2003
“… Si n-a achitat o factura
de spitalizare pentru o
traheotomie de urgenta.
Collet dadu din cap ,
amintindu-si o ancheta a
politiei la un restaurant
care omisese sa
mentioneze in meniu ca
reteta de chili includea si
ulei de arahide. Un
inocent om de afaceri
murise la masa, in urma
socului anafilactic, dupa
numai o inghititura.”
Definitie

• Este o afectiune mediata imuna la


un aliment

• Face parte dintre reactiile adverse


la aliment
Adverse Reactions to Food

Toxic (eg. Ciguatera) Non Toxic

Immune Non Immune


(Food Allergy) (Food Intolerance)

IgE Non-IgE Enzymatic Chemical Pharmacol


(eg eczema) (eg celiac)(lactase)(eg.salicylate) (histamine)

(Unknown ) ( Food Aversion)


Adverse Food Reactions
Immunologic
IgE-Mediated Non-IgE Mediated
(most common) Cell-Mediated
• Systemic
(Anaphylaxis) • Protein-Induced
• Eosinophilic
• Oral Allergy Enterocolitis
esophagitis
Syndrome • Protein-Induced
• Eosinophilic
• Immediate Enteropathy
gastrointestinal gastritis
• Eosinophilic proctitis
allergy • Eosinophilic
• Dermatitis
• Asthma/rhinitis gastroenteritis
herpetiformis
• Urticaria • Atopic dermatitis
• Contact dermatitis
• Morbilliform
rashes and
flushing
Sampson H. J Allergy Clin Immunol 2004;113:805-9, Chapman J et al. Ann
• Contact urticaria Allergy Asthma & Immunol 2006;96:S51-68.
Expunere

Predispozitie Genetica

Sensibilizare

Re-expunere

Simptome
Alergia Alimentara -
Prevalenta

• 5 – 8% la copii mici
• 2 – 3% la adolescenti si adulti
• 1-2% la adulti
• Cel putin 11 milioane de americani
afectati
• Prevalenta este in crestere (abrupt)
Prevalenta increstere in bolile alergice,
inclusiv alergia alimentara
Internarile dintre 1990/91 - 2000/01 in Anglia.

Timp de 11 ani nr.


total de internari a
crescut de la
0,02% la 0,06%.
(de la 1960 la 6752
din 49.300 internari
totale).

Gupta et al, BMJ 2003


8 Alergeni acopera 90% din alergiile
alimentare
• Arahide
• nuci de copac
(de ex. Nuci,
alune, etc)
• Peste
• Crustacee si
Moluste
• Oua
• Lapte de vaca
• Griu
• Soia
Inca 2 noi alergeni + conservant

Seminte susan Fructe si Legume crude


+ Sulfitii
Romania
Istoria Naturala a Alergiei Alimentare
 Alergia alimentare poate disparea cu virsta:
 Lapte – 20% (4 ani); 40% (8 ani); 60% (12 ani);
80% (16 ani)

 Ou – 10% (4 ani); 40% (8 ani); 65% (12 ani);


80% (16 ani)

 Arahide – 20%

 Nuci de copac – 10%


Normal larynx Laryngeal oedema
Simptomele Alergie

 Simptome Cutanate (U, AE, Ecz)


 Simptome Gastrointestinale
 Simptome Respiratorii (Wheeze)
 Simptome Orale
 Simptome Sistemice (SA)

29
Simptome de Alergie
Diagnostic

• Perioade scurte cu dieta de eliminare


• Anamneza + ex obiectiv (AHC, APP)
• Teste de provocare
• Teste cutanate
• IgE specifice din singe (RAST)
• Teste cutanate patch cu alimente
• Metode noi: microarray peptide
Testarea cutanata
Teste cutanate
Prezentare de caz
 Fetita de - 2 ani, cu sd diareic cronic, cu
agravare. Se interneaza intr-o sectie de
pediatrie. Diagnostic de Enterocolita acuta.
Se instituie regim alimentar cu brinza de
vaca. Se agraveaza (ATI), iar din simptomele
prezentate se poate diagnostica Socul
Anafilactic la proteinele din laptele de vaca.
 Test cutanat pozitiv la cazeina 14 mm
 IgE specific la cazeina 57 kUI/l
Sindroame Gastrointestinale
A. Sindromul Oral alergic
1- Edem al muoasei orale dupa ingestia anumitor
fructe proaspete si vegetale la pacientii cu alergie
la polen
2 – Alergenii sunt distrusi prin gatire
3 – Cauzate de cros-reactivitatea dintre polen si fructe/vegetale

4 – Rar progreseaza
dincolo de gura
Denumire
• Sindrom oral – Sindrom alergic oral (1987, de catre
Almot et al)
• Sindrom polen-fructe – Sindrom alergic polen-fructe
(polen-fructe-legume)
• Au mai fost utilizate: sindromul de urticarie de
contact la telina (1983); sindromul telina-morcov-
artemisia-condimente (1985); hipersensibilitate de
contact la alimente (2008); sindrom oral-polen (2003)
• Sindromul latex-fructe
Patogeneza
• Reactivitatea incrucisata (cross-reactivitatea) apare cind un Ab
specific format ca raspuns la un epitop reactioneaza cu unul similar
sau identic de la alt antigen

• Polenurile si fructele/legumele nu sunt legate botanic, dar contin


proteine homoloage conservate numite
pan alergeni (raspinditi frecvent in regnul vegetal si animal)

• IgE specific fata de aceste structuri comune cross-reactive intilnite


in polen si alimente derivate din plante

Current Allergy and Asthma Report 2008,8:413-17


Allergy: clinical relevance  “in vitro” testing
intra-allergenic heterogeneity allergen = mixture of allergen components

Component-resolved
Diagnosis (CRD)
B
A

E
C D
Ebo et al.,and
CRD University
ISAC | of
DeAntwerp
Boer,
Nieuwhof, Bons and 38
Menheere | April 23, 2013
Alergenii
(mesteacan si fructe)
RAST

classical ImmunoCAP assay


RAST1 40 µL
Single-analyte assay: single analysis of specific IgE directed against single
allergens, single allergen components or mixtures of allergens

ISAC (Immuno Solid-phase Allergy Chip )

ImmunoCAP ISAC (16 spots per mm2)

Multiplex assay: multiple analysis of specific


IgE directed against allergen components in one
single run
CRD and ISAC | De Boer,
Nieuwhof, Bons and 40 ISAC112 30 µL
Menheere | April 23, 2013
Storage protein

Storage protein
intra-allergenic heterogeneity
Storage protein

Storage protein

Profilin

Storage protein

Storage protein

Pathogenesis Related-10 protein

non-specific Lipid Transfer Protein

Component-resolved
CRD and ISAC | De Boer,
Nieuwhof, Bons and 41
Diagnosis (CRD)
Menheere | April 23, 2013
Complications Detecting specific IgEs - 1
intra-allergenic heterogeneity

inter-allergenic homogeneity

non-specific Lipid Transfer Proteins Ara h 9

Pathogenesis Related-10 proteins Ara h 8

Profilins Ara h 5

CRD and ISAC | De Boer,


Nieuwhof, Bons and 42
Pan-allergens
Menheere | April 23, 2013
Pan Alergeni
Cross-reactivi
• Larg raspinditi in regnul vegetal
• Sunt implicati in cross-reactiviatea IgE intre antigenii
dintre specii de plante neinrudite

• Protein e Vegetale implicate in sd alergic polen-fructe


(PFAS)
- Proteine legate patogenetic (PRs)
- Proteine de transfer a lipidelor (LTPs)
- Profiline
- Cross-reactivitatea prin determinantii carbohidrati : CCD

Current Allergy and Asthma Report 2008,8:413-17


Sd Artemisia-telina-condimente

Allergy 2006;61:461
Esofagita eozinofilica
Gastroenterita eozinofilica

1- Reflux , durere abdominala, diaree , satietate


precoce

2 – Caracterizata de infiltrare eozinofilica a tractului


digestiv
Tratamentul Alergiei Alimentare

• Evitarea, evitarea, evitarea


• Tratamentul simptomelor (AH1, GCS)
• Adrenalina/epinefina
• Anti-IgE
• Imunoterapie orala
• Alte terapii: tratament cu ierburi
Chinezesti
Evitarea alimentului/
Diete de eliminare pe termen lung

• Pt unele alimente pe viata (arahide,


fructe de mare, fructe)
• Pt alte alimente: se cistiga toleranta in
timp: la lapte in 2-3 ani, ou in 3-5 ani
• Citirea etichetelor!!!
• Imunoterapie orala induce toleranta
Alergiile medicamentoase

Sensibilizarea la medicament este frecventa, dar o


problema complicata in practica clinica

Multiple mecanisme de interactiune medicament-


gazda, multe slab cunoscute

Diagnosticul sensibilizarii la medicament este


dificil
Reactiile alergice la medicament sunt
subdiagnosticate/ supraevaluate
48
Introducere
- definitie-
Reactie Adversa la medicament include toate
consecintele terapeutice ale medicamentului
cu exceptia esecului terapeutic, otravirea
intentionata sau accidentala si abuzul.
World Health Organization

1 - Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma and Immunology, and the
Joint Council of Allergy, Asthma and Immunology. Executive summary of disease management of drug
hypersensitivity: a practice parameter. Ann Allergy Asthma Immunol. 1999 Dec;83(6 Pt 3):665-700.

49
Introducere
Reactii Adverse la Medicament
Tip A (predictibile)2,3 Tip B (nepredictibile)2,3
(80%)

 Supradozaj Nu depind de Doza,


 Efecte secundare Nelegate de actiune
 Efecte adverse farmacologica,
 Interactiuni intre Frecvent severe (pot cauza
medicamente moartea)
 Hipersensibilitatea (25%)

 Pseudoalergic

 Idiosincrazia

 Intoleranta (AINS)

2 - Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician. 2003 Nov 1;68(9):1781-90.
3 - Vervloet D, Durham S. Adverse reactions to drugs. BMJ. 1998 May 16;316(7143):1511-4.
4 - Gruchalla RS. Drug metabolism, danger signals, and drug-induced hypersensitivity. J Allergy Clin Immunol. 2001
50
Oct;108(4):475-88.
Clasification of Drug Allergy
Real life drug - penicillin
Comments Reaction Mechanism Gel &
Coombs
Skin test anaphylaxis IgE mediated Type I
desensitization

Non Anemia IgM,IgG Type II


nephritis Cytotoxic
Non Serum Soluble Type III
immunecomplex
sickness
Patch test Contact Delayed Type IV
hypersensitivity
dermatitis
Felt sick due to drug’s intake?

19.7% of the
inquired
mentioned
feeling sick after
taking a drug at
least once during
his/her life.

95% confidence interval: 13% - 26%


54
Medical confirmation of drug allergy

95% Confidence interval: 6% - 16%


55
Cele mai frecvente

• Analgezice (codeina, morfina, nonsteroidal


anti-inflammatory drugs =NSAIDs, de ex.
ibuprofen sau indometacin si aspirina)
• Antibioticele ca penicilina, sulfamidele, si
tetraciclina
• Miorelaxantele (anesteziei)
• Terapiile biologice

56
Diagnostic
• Istoric (corelarea dintre medicament si datele
din literatura! ) – nu totdeauna reala!!!
• Investigatii
1. in vitro: Immunoassays -Ig, triptaze;
Lymphocytes transformation test (LTT), Flow-
cytometry; Basophil activation test (BAT)
2. in vivo: skin tests, provocation tests
• Monitorizarea raspunsului (supravegherea)
Characteristic chronology of drug-induced eruptions.
separation at 1 hour into immediate or nonimmediate
reactions not sufficiently reflect large overlap between
pathophysiologically determined immediate- and delayed-type clinical
manifestations

Med Clin N Am 94 (2010) 711–725


Immediate reactions
Serum tryptase
Plasma histamine
Serum tryptase
24-hr Urinary histamine metabolite

0 30 60 90 120 150 180 210 240 270 300 330


An elevated level supports a diagnosis of anaphylaxis.
Normal levels do not exclude anaphylaxis.
RAST Testing
(sIgE in serum)
• Pt tehnica RAST, un allergen
cunoscut este legat la o baza de
polydextran. Serul este adaugat
si reactia specifica antigen-IgE
specific are loc si imobilizeaza
antigenul. Ab anti-IgE
radiomarcati se adauga. Nivelul
radioactivitatii este proportional
cu concentratia antigen-IgE
specific din ser.
Testul de Activare a Bazofilelor

Drug-HSA Negative control Positive control

Positive control: 52.5% CD63+, SI - 5501/386 = 14.2


Steiner, M. et al. J Vis Exp 2011 Positive drug BAT: 20.6% CD63+; SI - 1893/386 = 4.9
Teste de detectare a cel T specific anti-
medicament la pacientii cu reactii de
hipersensibilitate tardiva

Immunol Allergy Clin N Am 29 (2009) 537–554


HLA si Hipersensibilitatea la
Medicamente
Antibiotice - Teste cutanate
Antimicrobial drug Nonirritating Full-strength Dilution from full
concentration concentration strength

azithromycin 10 µg/ml 100 mg/ml 1:10,000

cefotaxime 10 mg/ml 100 mg/ml 1:10

cefuroxime 10 mg/ml 100 mg/ml 1:10

cefazolin 33 mg/ml 330 mg/ml 1:10

ceftazidime 10 mg/ml 100 mg/ml 1:10

ceftriaxone 10 m g/ml 100 mg/ml 1:10

clindamycin 15 mg/ml 150 mg/ml 1:10

cotrimoxazole 800 µg/ml 80 mg/ml 1:100

erythromycin 50 µg/ml 50 mg/ml 1:1000

gentamicin 4 mg/ml 40 mg/ml 1:10

levofloxacin 25 µg/ml 25 mg/ml 1:1000

imipenem/cilastin 0.5 mg/ml 500 mg/100 ml 1:10


meropenem 1 mg/ml 50 mg/ml 1: 50

nafcillin 25 µg/ml 250 mg/ml 1:10,000

ticarcillin 20 mg/ml 200 mg/ml 1:10

tobramycin 4 mg/ml 80 mg/2 ml 1:10

vancomycin 5 µg/ml 50 mg/ml 1:10,000


Khan DA. Drug Allergy. In Manual of Allergy & Immunology 5th Ed.
2012
Brennan et al., JACI 2009
deleanudiana@yahoo.com
Definitia Anafilaxiei
• Anaphylaxis – ana = impotriva phylaxis =
protectieia
• Sindrom cu mecanisme, prezentare clinica si
severitate variate
• Cu risc de deces.
• Frecvent este produs prin mecanism imunologic
(Tipul I HS)
• Include anafilaxia ne-alergica (anterior numita
reactie anafilactoida).
• Se datoreaza eliberarii de mediatori din bazofile
si mastocite.
WAO Nomenclature Review Committee JACI 2004
Incidenta
• Analiza datelor din studii publicate:
• 3.3 - 4 milioane de Americani.
• 1.433 – 1.503 americani au un risc de reactie anafilactica fatala.

Incidenta Bazata pe prescrierea de Epinefrina pt utilizarea inafara


spitalului
• Din Canada si Tara Galilor, UK.
• 0.95% din populatia din Manitoba, Canada.
• 0.2 la 1000 in Tara Galilor.
• Incidenta a creascut in Wales intre 1994 - +1999.

Neugut, Ghatak, Miller Arch Int Med 2001


Simons, Peterson, Black JACI 2002
Rangaraj, Tuthill, Burr, Alfaham JACI 2002
Factori
• Medicamentele (antibioticele, substantele
de contrast, anestezicele, miorelaxantele,
AINS etc)
• Alimentele (arahidele, fructele de mare,
laptele de vaca, ou, etc
• Intepaturile de insecte (albina, viespe, etc)
• Latexul
• Idiopatic
Cauze de anafilaxie
(alergice, dar ne mediate IgE)
Agregate Imune (Tip II HS)
• Imunoglobuline Intravenoase
• Dextran
Citotoxic (Tip III HS)
• Reactii post-transfusion fata de elementele celulare –
grupe ABO (IgG, IgM)
Degranulare directa a mastocitelor/bazofilelor (sau
alte mecanisme)
• Substante de contrast cu greutate moleculare mare,
Gaz Etilen oxide din tuburi de dializa, protamina,
ACE-inhibitori, substantele din membranele de
dializa:poli-acrilonitrile sulfonat, poli-
metilmetacrilat, opioide
Factori fizici: Efortul fizic, temperatura (frig/cald)
Medicamente ce pot influenta
(favoriza, reduce raspunsul terapeutic)

• Beta-blocantele
• Inhibitorii ACE
Semne si simptome

• Eritem Difuz • Aritmie Cardiaca


• Prurit Difuz • Greata
• Urticarie Difuza • Varsaturi
• Angioedem • Ameteala
• Edem Laringeal • Cefalee
• Bronhospasm • Senzatie de rau
• Hiperperistaltism • Pierderea cunostiintei
• Hipotensiune • Flushing

Kemp and Lockey JACI 2002


Cele mai Frecvente Semne si Simptome de
Anafilaxie: (indiferent de cauza)

Manifestation Percent
Urticaria/angioedema 87

Flush 50

Dyspnea/wheeze 46

Hypotension 30

Gastrointestinal 30

1. Lieberman P. Immunol Allergy Clin North Am. 2001;21:813-825.


Caracteristici
 Urticaria, angioedemul si flush sunt cele
mai
frecvente ( 80- 90%)
 Dar manifestarile Cutanate pot apare
ulterior
hTA sau pot fi absente!!!
 Urmeaza ca frecventa manifestarile
respiratorii (40% - 60%)
 Ameteala, pierderea cunostiintei (30% -
35%)
 Simptome Gastrointestinale (20% - 30%)
Lieberman In Allergy: Principles and Practice Mosby, 2003
Caracteristici
Cu cit apar mai rapid (de la contact)
cu
atit mai severe
 Apar la 5 - 30 minutes de la contact,
dar
si tardiv (ore)!!!
 Se rezolva spontan sau post terapeutic
in 30 min-2 ore, dar la unii poate
persisita, sau pot aparea recaderi
 Nu exista predictibilitate (ce
severitate
Lieberman In Allergy: Principles and Practice Mosby, 2003
Anafilaxie Recurenta si persistenta

• Recurenta sau bifazica intre 8 si 12 ore, la


aprox. 20%.
• Persoanele cu forma bifazica nu difera
clinic,
dar ar putea avea nevoie de mai multa
adrenalina/epinefrina initial
• Anafilaxie Persistenta poate dura 5 pina la
32 Lee and Greenes Pediatrics, 2000
Kemp and deShazo In: Allergens and Allergen Immunotherapy to
ore. Treat Allergic Diseases. Marcel Dekker, 2004
Diagnostic Diferential
 Reactii Vasovagale
 Flushing Idiopatic
 Mastocitoza
 Sindromul de activare a mastocitelor (MCAS)
 Sindrom Carcinoid
 Hyperventilatie indusa de Anxietate
 Globus hystericus
 Boala Serului
 Deficitul de C-1 esteraza inhibitor
 Socul cardiogen (de ex. infactul miocardic,
hipovolemic)
sau septic
 Sindromul Scombroid (intoxicatie cu peste)
Montanaro and Bardana JACI 2002
Tratament

I. Interventie Imediata (URGENTA MAJORA!)


a) Evaluarea cai respiratorii, respiratia, circulatia.
b) Administrare de Adrenalina/ EPI, 1:1000 dilution, 0.3
- 0.5 ml (0.01 mg/kg la copii, max 0.3 mg/ doza) IM,
Repetare , daca este necesar la 10-20 min.

Kemp and Lockey JACI 2002


Simons et al JACI 1998
Simons, Gu, Simons JACI 2001
Tratament
II. Masuri Generale
a) Pozitie decubit cu membrele inferioare ridicate.
b) Mentine libere caile respiratorii (Tub endotraceal sau
cricotirotomie).
c) O2, 6 - 8 litri/minut.
d) Sol salina, IV. Daca are hipotensiune severa - solutii
coloide.
e) Eventual garou la nivel superior penetrarii alergenului (ar
scadea
absorbtia alergen?).
f) Anti-histaminice H1 (eventual H2)
g) Bronhodilatatoare
h) Dopamina
i)Kemp
glucocorticosteroizi
and Lockey JACI 2002
Summary
Prognostic
Factor Poor Good
Dose of antigen (allergen) Large Small
Onset of symptoms Early Late
Initiation of treatment Late Early
Route of exposure Parenteral Oral*
β-adrenergic blocker use Yes No
Presence of underlying disease Yes No

* True for drugs, not foods


Profilaxie

• Anameneza corect
• Atentie la atopici/alergici/astmatici
• Testare (cutanata, evaluare IgE, BAT, de provocare)
• Daca a avut un soc: educare, purtare de Epi/Ana-pen
• Imunoterapie specifica (Desensibilizare)

berman In: Allergy: Principles and Practice. Mosby, 2003


Rezumat
• Boli alergice cutanate (urticarie, dermatita
atopica, dermatita de contact)
• Alergie medicamentoasa
• Alergie alimentara
• Socul anafilactic