Download Allergy 2

What a GP should offer after an
anaphylactic reaction
• Information about anaphylaxis, including the signs and
symptoms of an anaphylactic reaction
• Information about the risk of a biphasic reaction
• Information on what to do if an anaphylactic reaction
occurs (use the adrenaline injector and call emergency
services)
• A demonstration of the correct use of the adrenaline
injector and when to use it
• Advice about how to avoid the suspected trigger (if
known)
• Information about the need for referral to a specialist
allergy service and the referral process
• Information about patient support groups: Anaphylaxis
Campaign UK
Is it Anaphylaxis?
Masqueraders of anaphylaxis
• Vasovagal reaction (probably the most common masquerader)
• Laryngo-pharyngeal Reflux: Silent GERD – related to eating
– “difficulty breathing” /throat tightness”, lump in the throat
– Clues: sore throat, hoarseness, cough, excessive throat clearing
•
•
•
•
•
•
•
•
Vocal Cord Dysfunction
Panic attacks /Globus hystericus/ Hyperventilation Syndrome spectrum
Oral Allergy Syndrome (Pollen-food Syndrome)
Acute urticaria
Acute Asthma & acute urticaria (pollen-induced, pet-induced)
Scombroid fish poisoning
Hereditary angioedema
Other forms of shock (ie, hypovolemic, cardiogenic, septic) Flushing
syndrome
• Variants of Mastocytosis: Mast Cell Activation disease
• Autonomic epilepsy: Sudden episode of vomiting, flushing, sweating, pallor,
goose bumps
Can we identify patients at risk of lifethreatening allergic reactions to foods?
Anaphylaxis is defined as “a severe, life-threatening
generalized or systemic hypersensitivity reaction”
• 80% of adults recover spontaneously from foodinduced anaphylaxis despite not receiving adrenaline or
medical attention
• However, severe, life-threatening reactions do occur,
and these are unpredictable, resulting in a perception
of risk and therefore adversely affects quality of life
comparable to chronic illness like diabetes
• Due to the inability to identify patient at highest risk,
all anaphylaxis should be considered potentially fatal
and offered education & appropriate rescue
medication.
Who should be prescribed an adrenaline autoinjector?
In 2014, a European panel of experts (Muraro et al 2014) recommended that
adrenaline should definitely be prescribed where:
• There has been previous anaphylaxis triggered by food, latex, aeroallergens
or exercise; or where the cause is unknown (idiopathic)
• The patient has unstable or moderate-to-severe persistent asthma plus a
food allergy
• The patient has insect sting allergy where allergic reactions have been
moderate or severe
In addition, the panel made recommendations on cases where there have been
no previous severe reactions but there might be a risk of a severe one in the
future. The panel recommended that the treating doctor should consider
prescribing adrenaline where:
• There has been a mild to moderate reaction in the past to peanut and/or a
tree nut
• There has been a reaction to tiny traces of food
• The person with a food allergy is a teenager or young adult
• The patient has suffered a mild-to-moderate reaction and lives remote from
medical help.
Adrenaline Autoinjectors
•
•
•
•
Emerade (30 month shelf life)
150mcg pre-filled pen £26.94 (16mm needle)
300mcg pre-filled pen £26.94 (25mm needle)
500mcg pre-filled pen £28.74 (25mm needle)
• Epipen (18 month shelf life)
• 150mcg pre-filled pen £26.45 (13mm needle)
• 300mcg pre-filled pen £26.45 (16mm needle)
• Jext (18 month shelf life)
• 150mcg pre-filled pen £23.99 (13mm needle)
• 300mcg pre-filled pen £23.99 (16mm needle)
Emerade Adrenaline Autoinjector
• A 25mm needle is best and is suitable for all ages. In pre-term or very
small infants, a 16mm needle is suitable for IM injection. In some adults, a
longer length (38 mm) may be needed.
Dose
• The recommended adrenaline dose for the treatment of anaphylaxis is 510mcg/kg. Therefore a 300mcg dose is too low for most adults. NICE/BNF
recommends 500mcg in adults and children over 12 years for selfadministration. The UK Resuscitation guidelines for healthcare providers
recommend 500mcg for patients older than 12 years.
Proposal
• Emerade is used first line as the higher dose and longer needle length are
more appropriate for the majority of patients.
• Patients can be maintained on Jext or Epipen if they are used to this
device and the dose and needle length are not unsuitable for the patient.
• Patients are switched to Emerade by GP if longer needle length / higher
dose deemed clinically appropriate.
Urticaria & Angioedema
Vincent St Aubyn Crump FRCP
YHPA Immunology Symposium
21 May 2016
Spot Diagnosis?
…angioedema comes in all size, shape & forms
Lisinopril stopped in Feb 2016
Rx Amlodipine 5mg
IgE Mediated Urticaria & Angioedema
•Foods (e.g., peanuts, tree nuts, wheat, soy, milk, egg, shellfish, fish)
•Inhalants (e.g., animal dander, pollen)
•Insect sting or bite (Hymenoptera venom, fire ants, Triatoma)
•Medications (e.g., beta-lactam antibiotics, sulfa-containing medications)
•Contactants (e.g., latex, animal saliva)
Autoimmune Mediated (30-50% of CSU)
•Anti-FcɛRI antibody & Anti-IgE antibody
•Can be associated with Autoimmune thyroid disease
Direct Mast Cell Activated
•Neuromuscular blocking agents (e.g., succinylcholine, pancuronium, atracurium)
•Opioid narcotics (e.g., morphine)
•Radiocontrast media
•Vancomycin
Arachidonic Acid Metabolism
•Aspirin & NSAIDs
Stress
• Commonest cause of chronic urticaria & recurrent angioedema
Infections
•Viral (up to 62% of acute urticaria)
Physical Urticarias or Inducible Urticarias
•Cholinergic urticaria
•Dermatographism
•Delayed pressure urticaria
•Cold urticaria
•Solar urticaria
•Aquagenic urticaria
•Local heat urticaria
•Vibratory urticaria
Systemic Diseases
•Autoimmune disorders (e.g., systemic lupus erythematous)
• Cryoglobulinemia
* Neoplasia
Mechanisms of Urticaria
Urticaria
Spontaneous urticaria
• Acute spontaneous urticarial - lasting <6 weeks
• Chronic spontaneous urticarial – lasting >6 weeks
Inducible (non-spontaneous urticaria) or Physical Urticaria
• Symptomatic dermographism: moderate stroking of skin of volar aspect of forearm
with closed ball point pen – read in 10 minutes
• Cold urticaria -Cold provocation and threshold test (ice cube, cold water, cold wind)
Differential blood count and ESR or CRP cryoproteins rule out other diseases,
especially infections – melting ice cube in plastic bag for 5 min. & read in 10 min after
• Delayed pressure urticaria :Pressure test and threshold test – suspend 7kg weights
over shoulder for 15 min and read in 6 hours
• Heat urticaria Heat provocation and threshold test Solar urticaria UV and visible light
of different wavelengths and threshold test Rule out other light-induced dermatoses
• Vibratory Angioedema Elicit dermographism and threshold test (dermographometer)
Test with, for example, vortex Differential blood count, ESR or CRP Aquagenic urticaria
Wet cloths at body temperature applied for 20 min
• Cholinergic urticaria: Exercise for 30 min and hot bath (for 15 min after body temp
increase >1̊C over baseline– wheals during and after test
• Contact urticaria - Cutaneous provocation test. Skin tests with immediate readings,
for example prick test
Angioedema
• Angioedema is subcutaneous or submucosal swelling
• The main pathophysiological process is usually
confined to the subdermis; this is in contrast to
urticaria, which is a superficial dermis oedema and
inflammation.
• The release of inflammatory vasoactive mediators
such as histamine, serotonin and kinins, eg bradykinin,
is responsible for the inflammation, arteriolar
dilatation and eventual vascular leakage and tissue
swelling.
• Angioedema is present in up to 50% of pts with
chronic urticaria
Allergic Angioedema
• IgE-mediated (Mast Cell & Basophil mediator
release)
– Medications
• Penicillin,
• NSAIDs / Aspirin (few cases)
– Foods– particularly nuts, shellfish, milk and
eggs
– Venom sting & other insects
– Latex
– Contact (animal saliva, fresh fruit, vegetables)
Angioedema without urticaria
•
•
•
•
•
Bradykinin-induced (Angioedema without urticaria)
• Hereditary Angioedema,
• ACE-inhibitor & ARB
Leukotriene mediated: NSAIDs
Unknown mechanism eg Spontaneous Angioedema (Idiopathic): common triggers
• anxiety or stress
• minor infections
• hot or cold temperatures
• exercise
Hereditary Angioedema
– low levels of an enzyme (C 1 esterase inhibitor)
– complement C3, C4, C1 inhibitor
– Exacerbated by oestrogen
– Rx: Attenuated androgens (Danazol) prevent attacks & Icatibant (Bradykinin
Receptor Antagonist) for acute attacks
Acquired C 1 inhibitor deficiency :
– Lymphoma
– autoimmune disease such as Systemic Lupus Erythematosus (SLE)
Angioedema
Angioedema without urticaria
Causes of Angioedema at an Emergency
Department
ACE Inhibitor
Idiopathic
C1 Esterase Inhibitor
(Heriditary & Acquired)
Concomitant Ilness
(Infections etc)
Other drugs
Top 10 drugs/drug classes associated
with angioedema
•
•
•
•
•
•
•
•
•
•
ACE-inhibitors
Bupropion
(Zyban)
Non-steroidal anti-inflammatory drugs (NSAIDs)
Selective serotonin reuptake inhibitors (SSRIs)
other antidepressants
COX-II inhibitors
Angiotensin II receptor antagonists
Statins
Proton pump inhibitors
Vaccines
– West Midlands Centre of Adverse Drug Reactions
• Calcium Chanel Blockers e.g Amlodipine
ACE inhibitor-induced angioedema
•
•
•
•
•
•
•
•
•
•
ACE-inhibitor common cause of angio - ~1% or recipients (5% in blacks)
Account for 1/3 of cases of angioedema treated in emergency departments
Can occur with any ACE & is not dose-related
In >50% cases, angio starts during first week, but can start 10-15 years after
stable therapy
Angio commonly affects lips, tongue, upper airways (pharynx, larynx,
subglottis) or face -fatalities reported
Less common presentation is episodic abdominal pain & diarrhoea due to
intestinal angioedema (pseudo obstruction)
Urticaria & itching is notably absent
Management: discontinue & avoid all ACEi & cautious with Angiotensin
receptor blockers (ARB)
Episodes of ACE-induced angio can persist for up to 6 months
Antihistamines, steroids, and adrenaline usually ineffective or minimally
effective treatment. Icatibant (bradykinin receptor antagonist) useful in
some cases
Treatment of acute/intermittent
urticaria & angioedema
• Treat symptomatically- when required until resolution
• Use a non-sedating antihistamine, 2 tabs at first sign of symptoms
& continue 1-2 tabs od or bd until resolution & review need for Rx
– Cetirizine 10mg – cost-effective 1st line: OTC
– Loratidine 10mg – cost-effective alternative: OTC
– Fexofenadine 180mg – suitable alternative if above not effective
• Patient diary recording & photos:
– Characteristics of episodes
– Frequency & duration
– Suspected triggers
• Review patient diary and:
– Implement allergen avoidance measures (foods/drugs) if appropriate
– Consider referral/discussion with Allergy/Immunology if allergy
strongly suspected
Chronic Spontaneous Urticaria
• In majority is not an allergic condition – is
spontaneous, and due to a mast cell activation
disorder
• Is self-limiting
– 50% resolve after 6 moths
– 70% resolve after 3 years
– 90% resolve after 5 years
– 92% resolve after 25 years
Chronic spontaneous urticaria & angioedema
(CSU) & chronic inducible urticarias (CIndU)
•
•
•
Chronic urticaria & angioedema defined by the presence of swellings and/or
wheals, usually on most days of the week for longer than 6 weeks
In most cases pathogenesis is incompletely understood
– An exogenous aetiology can be identified in only 10% of patients
– In majority, this is not an allergic condition; rather it is spontaneous and
thought to be due to a mast cell disorder
– ~30% of patient is triggered by an autoimmune process (Anti-IgE
antibody) & can be associated with Autoimmune Thyroid Disease
– Although not causative many factors exacerbate the condition like:
• Stress
• Aspirin & NSAIDs
• Infections
• Physical stimuli eg a hot shower
Management is symptomatic: antihistamines at correct dosage are effective
in vast majority of patients if stress & other non-specific triggers are
addressed.
Stepwise management plan for CSU &
CIndU
• Mild/infrequent episodes: non-sedating antihistamine (e.g.
cetirizine/loratidine/fexofenadine) on a prn basis
• Moderate/Severe /frequent episodes: regular Rx: start with 1 tab od,
and incrementally increase up to 4 tabs daily ( 2tabs bd); leave 1-4
weeks between each incremental step
• If not controlled from above: add montelukast 10mg od or ranitidine
150mg bd
• Once complete control achieved, remain on corresponding step for
~3-6 months before stepping down
• If at any stage urticaria/angio recur go back to previous stage for 3-6
months (no need to refer)
• Advice to seek emergency help if angio is associated with breathing
compromise
• Very rarely a brief course of prednisolone (e.g. 20-40mg daily for 3
days) to control severe episodes
• Refer if patient remains uncontrolled despite maximum treatment
– NWACIN Referral & management pathway for Urticaria; April 2016
When to refer Urticaria with or
without Angioedema
• If individual lesion last >24 hrs and leave bruising or
scarring (esp on lower legs) Refer to Dermatologist:
Urticarial vasculitis
• Refer to Allergy/Immunology if:
– Reasonable suspicion of a specific allergic trigger
– Additional features suggestive of anaphylaxis
– Angioedema not ACE-induced or ACE-induced persisting after 6
months
– Acute urticaria not resolved with adequate dose of nonsedating antihistamine daily
• Suggest patient diary recording episode characteristics, frequency,
duration, suspected triggers
– Chronic Urticaria or inducible urticaria not resolved following
stepwise management plan
Treatment options for Chronic urticaria
Immunosuppressants
Add Anti-IgE antibody
- Cyclosporine
Omalizumab 300mg s/c
- Prednsione
Add Montelukast (LTRA) 10mg
nocte OR if angioedema Tranexamic acid
Step 2: Add H2 blocker: Ranitidine 150mg bd
- Dapsone
or
Doxepin
Or
Add Vitamin D 2,000 IU or 5000 IU per day based on Vit D
level
Step 1: Second generation Lower sedating antihistamines x4 regular dose :
fexofenadine 180mg 2tabs bd,
levocetirizine 10mg bd,
Loratidine 20mg mane & cetirizine 20mg nocte
Montelukast (LTRA)
• Leukotriene receptor antagonists for chronic
urticaria: a systematic review de Silva et al
– Allergy, Asthma & Clinical Immunology 201410:24
– 10 eligible studies
– LTRA are effective add-on therapy to antihistamines (NOT as monotherapy), and their use
in patients responding poorly to antihistamines is
justifiable.
Treatment of Urticaria: Low-sedation
antihistamines efficacy
• Crossover studies comparing the suppression
of skin wheal and erythema formation induced
by intradermal histamine injection after a single
antihistamine dose suggest the following order
of inhibitory effect:
– (1) levocetirizine,
– (2) cetirizine,
– (3) terfenadine (withdrawn)
– (4) fexofenadine, and
– (5) loratadine.
Antihistamine: cost
•
•
•
•
•
•
Cetirizine (30) £1.05
Loratadine (30) £1.07
Levocetirizine (30) £4.12
Desloratadine (30) £1.63
Fexofenadine 120mg (30) £3.50
Fexofenadine 180mg (30) £4.87
Other treatments of Chronic urticaria
• Omalizumab (Ani-IgE) 300mg s/c monthly x6
(£3073.80 ex VAT) as add-on
• Doxepin 10-25mg nocte (tricyclic antidepressant)
• Vitamin D
• Dapsone
• Hydroxychloroquine (Plaquenil)
• Cyclosporine,
• Plasmapheresis and intravenous immunoglobulin
• Other agents used include colchicine,
sulfasalazine, warfarin, and methotrexate
Urticaria severity: Urticaria Activity Score
• The UAS7 is the sum of the average daily
UAS over 7 days
• NICE recommendation for Omalizumab is
a weekly urticaria activity score >28
Psychological stress & Urticaria
• “I was so stressed I broke out in hives”
• There is a growing appreciation of the link
between the mind, the immune system, and the
skin
• The skin and the nervous system are derived
from the same embryologic layer
• Relationship between post-traumatic stress
disorder and the incidence and severity of
chronic idiopathic urticaria.
• …planting a seed that somatic symptoms respond
to stress reduction techniques
Psychological stress & (chronic)
urticaria
• Psychological stress exacerbates chronic
urticaria through a variety of mechanisms,
including:
– heightened basophil response to
• corticotrophin releasing factor &
• adrenocorticotropic hormone (ACTH) and
– a derangement of the hypothalamic-pituitaryadrenal (HPA) axis
– (Dyke SM, Carey BS, Kaminski ER. Clin Exp Allergy.
2008;38(1):86-92).
Management following admission for
angioedema: NICE
•
Following hospital treatment for angio-oedema:
– Try to identify the underlying cause so that further episodes can be avoided.
• For people taking an angiotensin-converting enzyme (ACE) inhibitor stop treatment immediately.
Consider starting an alternative drug treatment. If possible avoid angiotensin-II receptor antagonists
as these can also trigger episodes of angio-oedema.
– Ensure that treatment has been offered with cetirizine, fexofenadine, or loratadine for peristent or
recurrent symptoms. Based on an assessment of the underlying cause, and the duration of symptoms
before treatment, treatment may be prescribed either:
• As required, if symptoms were short lived and frequent recurrence thought unlikely.
• Or, regularly, if symptoms are persistent or likely to recur frequently.
– Advise seeking immediate medical help (dial 999 or attend accident and emergency) if symptoms recur
and progress rapidly, or symptoms of anaphylaxis develop.
– Ensure the person has been referred to an immunologist or allergist unless there is an identifiable and
avoidable cause for angio-oedema such as an allergic or non-allergic drug reaction. For people
experiencing angio-oedema while taking an ACE inhibitor, referral is only required if symptoms persist or
reoccur 6 months after stopping treatment, when another cause for angio-oedema should be suspected.
– For people awaiting specialist review who are at risk of severe anaphylaxis, seek specialist advise about
stopping beta-blockers (if they are on them), and prescribing an adrenaline auto-injector device for them
to use in the event of anaphylaxis before their hospital appointment.
• People at high risk includes people with co-existing asthma, chronic obstructive pulmonary disease,
heart disease, and people who have experienced angio-oedema with trace amounts of an agent.
Quiz
• Urticaria & angioedema
– What is the arbitrary (cut-off) duration for acute & chronic
urticaria?
– What proportion of CSU will resolve completely in 6m?
– In what proportion of patients with CSU will an exogenous
cause be found?
• Anaphylaxis
– When was the term anaphylaxis coined?
– Name one of the organs which must be involved for
anaphylaxis to be diagnosed?
– What does anaphylaxis mean?
YHPA Immunology Symposium
Anaphylaxis
Urticaria & Angioedema
Vincent St Aubyn Crump FRCP
The Samlesbury Hotel
Saturday, 21st May 2016
Thank You
Antihistamines in anaphylaxis:
– Should patients presenting with mild systemic symptoms involving 1 or more systems eg.
urticaria with mild GI cramping be treated with antihistamines or adrenaline?
In anaphylactic deaths the median time to respiratory or cardiac arrest was:
• 30 minutes for foods,
• 15 minutes for venom, and
• 5 minutes for iatrogenic (drug-induced)reactions
In another study of fatalities, death occurred within 60 minutes in 13 of 25
cases
• fexofenadine (180 mg) given by mouth failed to exhibit any inhibitory
effect on histamine-induced wheal and flare at 30 minutes and did not
exhibit a 50% suppression of wheal and flare until over 100 minutes after
administration.
• Diphenhydramine 50 mg administered intramuscularly did not show a
50% reduction in skin test expression until 51.7 minutes, and
• diphenhydramine 50 mg administered orally did not demonstrate such a
reduction until 79.2 minutes after administration (25
….it is improbable that patients experiencing anaphylactic events
would be protected by antihistamine or corticosteroid
Severe drug-induced anaphylaxis in Europe
Allergy Vigilance Network from 2002 - 2010
6 deaths (1.8%)
• 2 Amoxicillin injxs (1 in the fetus)
• 2 Suxamethonium injxs
• Hydroxycobalamin injx
• ACE-inhibitor
Associated drugs enhancing
severity of anaphylaxis:
• β-blockers (11 cases, 3.3%),
• angiotensin-converting enzyme
(ACE) inhibitors (10 cases, 3%),
• angiotensin II receptor
antagonists (ARA, four cases,
1.2%),
• NSAIDs or aspirin (eight cases,
2.4%), and
• an association of β-blockers
with ACE inhibitors or ARAs
(nine cases, 2.7%).
Drugs causing severe anaphylaxis
84 different drugs incriminated:
• Antibiotics 165 cases – 49.6%
– Betalactams 138 cases
– Quinolones 15 cases
• Muscle Relaxants 36 cases
– Suxamethonium 18 cases
• NSAID & aspirin 33 cases 9.9%
• Acetaminophen / Paracetamol 13 cases – 3.9%
• Contrast Media 14 cases
– Gadolinium-based CM 9 cases
– Iodinated CM 5 cases
Indication for prescription of second
adrenaline autoinjector
• Co-existing unstable or moderate to severe, persistent
asthma and a food allergy
• Co-existing mast cell diseases and/or elevated baseline
tryptase concentration
• Lack of rapid access to medical assistance to manage an
episode of anaphylaxis due to geographical or language
barriers
• Previous requirement for more than one dose of adrenaline
prior to reaching hospital
• Previous near fatal anaphylaxis
• If available auto-injector dose is much too low for body
weight
– Expert opinion (no RCT)