Category Archives: Immunology

Hymenoptera venom allergy

Allergy, General paediatrics, Immunology

ie bee/wasp. A common cause of anaphylaxis, and interestingly, not related to atopy.  Reactions can be immunological (IgE or non IgE), or non-immunological (toxic). 

Severe reactions related to allergy but also number of stings, insect type, cardiovascular/respiratory disease and also mastocytosis.

Whether it is bee or wasp or other is sort of important, from the point of view of cross reactivity and risk. Several major allergens eg hyaluronidase, phospholipase A2. Apid (bee) hyaluronidase is 50% identical to vespid, so good chance of being allergic just to one and not the other.  Vespids subdivides into Vespa=hornets (found in UK, biggest, 35mm, reddish brown head); Vespula=wasps; and Dolichovespula (“short headed wasps” – harder to distinguish, “shorter distance between eyes and upper jaws”!). These 3 vespid types cross react strongly, so likely to be allergic to all.   “Yellowjacket” is American name for wasps.

Bumblebee PLA2 is 53% identical to honeybee PLA2, so not necessarily cross reactive!

Polistes=”paper wasps”, distinct from other vespids, Southern Europe only (so far) – large, long legs, not esp colourful. Limited cross reactivity to wasps/hornets, thankfully. 

Ants are also hymenoptera!

Clinical

  • “Normal” local
  • “large” local = >10cm swelling, plus >24hrs. Blisters sometimes present). Mech prob toxic, but sometimes evidence of IgE mediated mechanism,
  • systemic toxic (haemolysis, nephropathy, coagulopathy – rare, usually from multiple stings)
  • systemic +/- anaphylaxis [usually igE, rarely short term IgG, or complement activation by IgG-venom complexes]
  • (plus “unusual”).

Wasps and hornets not as fuzzy as bees. Was a barb left behind? Bees, not wasps. Multiple stings at the same location? Wasp, not bee.

Systemic reactions should be assessed by allergy specialist, including skin prick tests, total IgE and baseline tryptase tests.

  • rapid onset generalized urticaria and/or angio-oedema,
  • bronchospasm
  • laryngeal oedema
  • hypotension (collapse, loss of consciousness).

Hypotension is the dominant feature and may occur alone.

Risk factors for outcome of anaphylactic reaction:

  • age,
  • CVS disease/drugs,
  • insect type,
  • time interval between stings (short interval increases risk of systemic reaction to second sting),
  • number of stings,
  • severity of previous reaction,
  • elevated mast cell tryptase, else known mastocytosis.

Bee allergic at higher risk of systemic reaction than vespid allergic. Hornets risk seems to be esp high.

Frequent stings can induce tolerance (but probably needs more than 200 per year!). 

Venom IgE >1 had 12x risk of anaphylaxis (beekeepers, regardless of previous history). Pos skin test (adults without history of anaphylaxis) had 17% risk, cf 0% of neg skin test [so negative test v reassuring, but risk still low even if you are pos, which would be unusual in most kids]

Majority of fatalities have significant cardioresp co-morbidity. 40-85% of fatal reactions had no documented history of previous anaphylactic reactions.

Mild systemic reaction previously gives 18% risk of subsequent systemic reaction (kids). Compare after large local – 5-15%, so sl higher but not much. Children tend to have mild systemic reactions, cf most adults get resp or CVS symptoms.

Several case reports of severe reactions in mastocytosis; even without mastocytosis, high basal tryptase seems to increase risk of anaphylaxis.

Testing

Even when SPT pos, 25-84% of subjects do not react to subsequent sting!
 
Similarly, up to 22% of those with neg tests will have systemic reaction in future. [Allergy 2005: 60: 1339–1349]

Test all with systemic reaction, not recommended otherwise. If not witnessed? Only really useful to distinguish bees vs wasps (says the Anaphylaxis Campaign)!? Unless you’re a bee keeper, wasps are the one you are most likely to be stung by.

Skin prick testing more sensitive/specific. Probably sensible to leave a month or two between the event and testing else false negative due to “refractory period”. This period can sometimes be longer so consider repeating if good history.  If negative, try IgE; then intradermal ( with 0.001-1mcg/mL solution  -seems to have higher sensitivity).

Stepwise skin testing with 0.01-100mcg/ml solutions incrementally recommended. 

Some people will be persistently negative on testing, probably due to being allergic to an unusual protein. Consider systemic mastocytosis as a differential. 

Family history of venom anaphylaxis is a common cause of concern.  Unfortunately, there is no point testing other family members – you are unlikely to test positive if you have never been stung.

Specific IgE levels (if you do test positive) only vaguely correlate with anaphylaxis risk (not statistically significant) [Allergy 62(8): 884-889, August 2007]. However, having low total IgE (<50kU/l) predicts anaphylaxis (not v sensitive, only explains 25%), whereas high total IgE (>250) protects (very specific)!

Serum IgE appears within a few days of sting, begins to decline at a variable time – wait long enough, and no IgE may be detectable. Double positivity to bee/vespid could be genuine cross sensitivity but might be cross reactivity of IgE to epitopes of unknown clinical significance.

Baseline serum tryptase over 11 has high positive predictive value for anaphylaxis but is not very sensitive. Good for picking up mastocytosis though!

So you may be able to find the occasional person who seems to be at particular risk (high tryptase, low total IgE), or relatively protected (high total IgE) but you will still miss most cases of anaphylaxis.

Immunoblotting, basophil activation tests etc sometimes used if others tests negative. But sens/spec generally not known.  

High basal tryptase may increase risk of reactions with VIT but still indicated.

Give allergy plan and prescribe Adrenaline if severe systemic reaction, consider if moderate. 

If successful VIT, still get adrenaline if further symptoms, continued exposure, high tryptase.

[BSACI guidelines – Clinical & Experimental Allergy. Volume 41, Issue 9, September 2011, Pages: 1201–1220 doi/10.1111/j.1365-2222.2011.03788.x]

Immunotherapy

See Venom immunotherapy.

Honey allergy

Reported, in most cases appears to be due to pollens contained in the honey, or at least allergens highly cross reacting with pollens. But in a minority, does appear to be due to bee derived components. Type of honey will determine what pollens are contained in it; commercial honey often contains v low amounts due to production techniques.

Prevention

Risk of sting related to zone, climate, temperature, outdoor activities etc. Some repellents marketed as effective against wasp/bee (IR3535 (Ethyl butylacetylaminopropionate) eg Jungle Formula “outdoor & camping”) but most creams/sprays (DEET, Citronella oils etc) are for biting insects (midges, mosquitoes etc), not stinging. Bees/wasps generally not interested on landing on your skin anyway!  Sting because they are threatened!  

Avoid opening windows, avoid rubbish bins, tidy away food/drink (esp sugary) .  Calmly walk away!

Keep skin covered. Keep surfaces, mouth/face/hands clean of food residues after eating!!!

Raid-type killer sprays for environment.

Patient Support

Anaphylaxis campaign have insect venom leaflet.

Ocular allergy

Allergy, General paediatrics, Immunology

Differential of eye allergy includes tear film dysfunction, infection, autoimmune/inflammatory conditions, blepharitis, dry eye.

Severe -2 of vision disturbance, impairment of daily activities (leisure, sport, school, work); troublesome symptoms.

Perennial conjunctivitis usually related to house dust mite (HDM), animal dander, moulds else multiple. Itch characteristic, as per seasonal conjunctivitis, findings non-specific eg tearing, redness, eyelid swelling, small papillary hypertrophy of tarsal conjunctiva. Neither has corneal involvement.

Beware pain, photophobia, visual disturbance, grittiness or foreign body sensation.  These can indicated Vernal keratoconjunctivitis, which does affect the cornea (warm climates eg Mediterranean/Africa): typically boys aged 4-12yrs, T cell and IgE combined, improves after puberty. Severe itching, exacerbated by nonspecific stimuli eg wind, dust, sun. Cobblestone appearance of tarsal plate (ie inside upper eyelid) else limbic thickened and opacified +/- white/yellow gelatinous deposits (more typical of tropical form).  Can get corneal ulcers.

Atopic keratoconjunctivits is also rare, the eye can be the only affected area cf atopic dermatitis. Hall mark is fissured eyelid. Staph colonization contributes. Limbus and cornea can be affected.

Giant papillary – associated with contact lenses.

Contact blepharoconjunctivitis is eyelid itching, oedema, eczema with less in the way of conj redness.

Investigations for ocular allergy

Skin prick testing incl moulds. Consider latex. Else IgE.

Conjunctival provocation test can be done with standardized allergens – defer if on local or systemic antihistamines or anti-inflammatories, contra-indicated if uncontrolled asthma.  Ideally when asymptomatic and eye not inflamed! Dilute extract to obtain several lower concentration solutions (last up to 6 hours at room temp).  Administer 20microl dose at 30 min intervals at infero-external quadrant of right eye.  Left eye is control!  Have local antihistamine and steroids available, in addition to usual systemic medicines.  Only 1 reported case of anaphylaxis!

Patch test for non-IgE. Else Conjunctival cytodiagnosis eg eosinophil infiltrates.

Treatment and prevention –

  • Avoid allergens, protect eye with sunglasses.
  • Lubricants and cold compresses are good.
  • Topical antihistamines eg azelastine, olapatadine but also Lodoxamide, ketotifen.
  • Mast cell stabilizer (ie cromoglycate) needs 2/52 preloading and multiple doses per day, plus stings! So poor compliance.
  • Systemic antihistamines if other symptoms else may be excessively drying.
  • Topical steroids should be avoided except where cornea involved, ie VKC, AKC, and then only in short pulses.  Twice daily steroids for a month or more raises concern about glaucoma, cataracts.
  • Ciclosporin drops oily, supply probs – veterinary products used! Tacrolimus not available in drops; cream burns a little but gets better.

Nasal steroids work well for eye symptoms and appear to be safe.

For blepharitis, eyelid hygiene, emollients, 1% hydrocortisone.

[Leonardi, Allergy 67 (2012):1327]

Adrenaline Autoinjectors

Allergy, General paediatrics, Immunology,

viz Epipen, Jext, Emerade, AUVI-Q etc.

Who needs one?  Anyone at risk of anaphylaxis, is the simple answer.  But there are no reliable ways of identifying who is at risk of anaphylaxis!

There is also a big problem with them not being used even when they are available.

Who needs one?

EAACI position paper – see Anaphylaxis management.  Only a couple of absolute indications, otherwise a risk assessment. 

2021 Expert working group – MHRA set up after further coroner’s inquests into anaphylaxis deaths, following European safety review in 2015.  Recommendations are:

  • Early adrenaline.  Which means teaching families/children recognition of signs. 
  • Need for 2 pens emphasized.
  • Brand specific training
  • Key messages on packaging eg “don’t delay”, “use second pen if necessary”
  • Posture detailed – “lie down with legs up”, “sit up if breathing difficult but don’t change position suddenly”, “stay lying down [regardless of whether you feel better or what people tell you to do]” 
  • Wider availability of AAIs in public places likely to be beneficial but this would require legislative amendment as well as public training, and concerns about storage conditions and supply would need to be addressed.
  • Dosing errors in hospital common, but given pressure on AAI supply may not be great solution. Other solutions would be labelled kits, pre-filled syringes, different system of labelling adrenaline (!).
  • Reporting of device related adverse events, and anaphylaxis events (including re-establishment of fatal anaphylaxis registry).

Technique

Patient should lie down (but if respiratory symptoms then may be more comfortable sitting). Video available at Epipen and Jext websites. 3 minute training video with more explanation on Youtube. Or scan this:

  • Remove safety cap (Blue for Epipen, Yellow for Jext).
  • Hold in fist, avoid touching ends to reduce risk of accidental self injection.
  • Jab orange (Epipen) or black (Jext) tip firmly into upper outer thigh, through clothing if necessary but avoid seams and pocket contents eg coins, mobiles – clicks as it activates.
  • Hold for 3 secs (Epipen), 10 secs (Jext).
  • Previous advice was to rub area (probably now white) vigorously for 10 seconds. Adrenaline causes vasoconstriction in skin, but vasodilatation in muscle so should be absorbed as long as IM.  Not specified now.
  • Phone 999.
  • Dispose of device safely (device is self sheathing).  Note that some drug left behind, which is normal, and that pen cannot be reused!).
  • Repeat after 5 minutes if necessary. Use a different leg!

Training checklist (from GOS):

  • When to use it
  • How to use it
  • When to carry it ie at all times!
  • Storage/disposal – should be protected from heat and light
  • Expiry date – reminder service available from support website (link above)
  • Friends/babysitters aware?
  • School aware?
  • School trained and have pen?
  • Medicalert bracelet/watch/necklace – other brands available

They come in two different doses – standard strength is 0.3 mg, there is  a 0.15 mg strength prescribed for younger children (15-30kg). Emerade (not currently available) gcomes in a 0.5mg strength for adults and children over 12, which is a more appropriate dose for bigger people viz over 60kg.

If patient is under 15kg,  CYANS guidance is that over 7.5kg, the potential benefit outweighs the risk.  For those under 7.5kg, need to balance risk of anaphylaxis with risk of drug error from drawing up adrenaline from vial with syringe and needle.

Epipen has 18 month shelf life, self sheaths, and has a window to show ready to use. Blue safety cap, orange needle end. JEXT pen similarly self sheathing, coloured window to show whether it is live or not, 24 months shelf life. Yellow safety cap, black needle end. Same needle length.

Anapen has been discontinued.  Had a shorter needle, different technique – remove caps from both ends, hold against leg, put your thumb over the end and press red button.

Emerade pen has safety cap over needle end – this is different from the other types but is logically simpler. Needle is 25mm long cf 15mm Epipen/Jext.  Currently off market due to reliability of activation concerns.

Number of Pens

2018 MHRA review recommends 2 pens available at all times, and made the recommendation directly to families so they can demand them from their doctor!  BSACI (2016) suggested children should in most cases just get 2 pens, 1 for home and 1 for school, but this was contradicted by later European Medicines Agency (EMA) and previous NICE guidance.  Still not clear why they should ever by prescribed in single rather than twin packs…

European medicine agency review (legally binding in EU) concluded that:

  • due to uncertainties about the site of drug delivery and the speed of adrenaline action within the body, it is recommended that healthcare professionals prescribe 2 auto-injectors, which patients should carry at all times
  • the needle length of the device is now stated in the product information because this may be an important factor for the prescriber to consider when choosing a suitable auto-injector
  • the training of patients and their carers in the correct use of the product is important and manufacturers were required to update their educational materials
  • manufacturers should carry out studies in humans to more fully understand when and how much adrenaline reaches the blood stream, and how quickly and effectively it acts on body tissues when given through an auto-injector

EAACI guideline says number of pens should be guided by individual assessment, and BSACI also allow that 2 pens may be more appropriate in some cases, eg obesity, previous need for 2 doses, remoteness etc. There has been good evidence published indicating that one-third of children with anaphylaxis require a second dose of epinephrine (Kornblat P, et al Allergy Asthma Proc. 1999; 20: 383–6), and deaths have occurred despite a single injection, but most of these reports describe subcutaneous adrenaline use, rather than intramuscular use. Dose is more likely to be an issue with big teenagers (eg over 45kg).

If you carry your pen, know how and when to use it, then you are doing to do significantly better if you have a bad reaction than most other people, so don’t get too hung up on how many pens!

Spare pens in school

New legislation (2017) allows schools to obtain without prescription spare pens.  These can be used if the pupil’s own pen is not immediately available or already given.  Note that children with food allergies are not always prescribed adrenaline auto injectors but may still be at risk of anaphylaxis.  The spare pen can be used in such children if:

  • The child’s care plan confirms child is at risk of anaphylaxis
  • A health care professional has authorised use of the spare pen in an emergency
  • The child’s parent/guardian has provided consent for a spare pen to be administered

Note that advice on using pens can be given over the phone by emergency services, if it is made clear pens are available.

Further information about spare adrenaline pens, and advice on reducing the risk of reaction sin school, treating reactions in school, staff training etc can be found at https://www.sparepensinschools.uk/

Needle length

Doing ultrasounds of thighs shows that in a significant proportion of people, including children under 5 with high BMI, the distance to muscle is more than 15mm (and not including any clothing). 82% of the obese children studied had skin surface to muscle depth greater than needle length. This was only true for 25% of the non-obese children. 3/4 the way down the thigh, only 17% of obese children and 2% of those not obese. Arkwright, Royal Manchester Children’s Hospital –  2013 Annual AAAAI meeting.

Some suggestion from injection models that “jet” of adrenaline penetrates significantly deeper than needle alone, that the angle, force used, whether the device is spring loaded or not, all potentially affect depth. So concerning, especially given the cases where multiple injections have failed to prevent death (eg Natasha Ednan-Laperouse).

Emerade had longer needle (25mm) but not currently available.  So inject in lower lateral thigh?

2015 European medicine agency review discussed above concluded that training remains the paramount issue, although further research into needle length should be done.

2021 Review found that blood adrenaline levels actually higher after Epipen and Jext cf

Failure to use

In a prospective UK study of children prescribed AAI for at least a year, the most common reasons given by patients for not using their AAI (245 episodes of anaphylaxis, AAI used in only 16.7%) were ‘thought adrenaline unnecessary’ (54.4%) and ‘unsure adrenaline necessary’ (19.1%). Device not being available only mentioned in 5%.

In 2002 Australian retrospective study of patients with previous anaphylaxis, shortness of breath usually recognised as anaphylaxis symptom but less commonly upper airway or cardiovascular symptoms/signs. Half forgot the need to remove safety cap and hold for 10 seconds in scenario. 71% of anaphylactic reactions were not treated with AAI, even though AAI was available in most cases. About half of those needed adrenaline treatment in hospital (which was rare in AAI treated cases).

In a 3 year Canadian study of 1500 ED episodes, almost 50% of adults were not treated with epinephrine in or outside of the hospital.  Slightly better for kids, 28.7%.  Almost all of these children had been prescribed auto-injectors.  The need for multiple doses in ED was less in those who received epinephrine outside ED.  [Allergy, Asthma & Clinical Immunology 2014, 10(Suppl 2):A3]

In a Canadian email survey of 1885 anaphylaxis survivors (adults and kids, food and insect etc), 73% did not give epipen.  Most common reason for not giving, was that an antihistamine had been given first.  Only 28% gave reason as being that they did not have epipen! 13% judged reaction as mild.  41% of epipens were given by someone other than patient, mostly family of children.  53% of epipen users had previously used one before.  [simons, clark, camargo – JACI 2009:124;301 doi:10.1016/j.jaci.2009.03.050]

Failure to prescribe

In an online survey presenting 10 paediatric allergy case histories to paediatricians (all were severe, although only 1 case specifically mentioned anaphylaxis).  There was significant variability in prescribing practices. Although all allergists and generalists prescribed an autoinjector (94.4% and 92.6%, respectively) or would offer the patient a choice about autoinjectors (5.6% and 7.4%, respectively) in the case specifically mentioning anaphylaxis, many cases had almost no consensus on prescription of adrenaline autoinjector. The prescribing patterns of allergists and generalists showed no significant differences for 9 of the cases. For the remaining case, which described a child with oral allergy syndrome, all specialists (n=54, 100%) reported that they would not prescribe an autoinjector (in line with guidelines) compared with only 20 (74.1%) of generalists (p<0.001).  [Johnson MJ, Foote KD, Moyses HE et al. (2012) Practices in the prescription of adrenaline autoinjectors. Pediatric Allergy and Immunology 23: 124-7]

In a survey of all GPs in Scotland, 90% of the 613 respondents had prescribed adrenaline autoinjectors. However, only 49% of prescribers were confident in use of these devices, and only 17% had access to a trainer pen for demonstration to patients. If called upon in an anaphylactic emergency (experienced by 36% of respondents), only 50% of respondents would use the appropriate dose and 14% would use an inappropriate route of administration (subcutaneous or intravenous).  [Lowe G, Kirkwood E, Harkness S (2010) Survey of anaphylaxis management by general practitioners in Scotland. Scottish Medical Journal 55:11-4]

Failure to Use – Doctors

When scenarios presented to junior doctors (same questions posed 10 years earlier) – all recognized need for adrenaline in anaphylaxis scenario but dose often wrong and 25% gave adrenaline IV.  For non-anaphylactic scenarios, adrenaline frequently recommended eg inhaled peanut.  Not much improvement over decade.  [Postgrad Med J 2015;91:3-7 doi:10.1136/postgradmedj-2013-132181 ]

Editorial discusses how doctors know that adrenaline is required in anaphylaxis, but that this knowledge is often not translated into practice. Many of these doctors had had ALS training; most had not worked in an emergency department.  Simulation?  Australian experience.  Booster sessions?

Accidental self-injection

See accidental adrenaline self-injection.

Anaphylaxis – management

Allergy, General paediatrics, Immunology,

Management of anaphylaxis involves treating the acute emergency, in the community first (see adrenaline autoinjectors), then in hospital, and then arranging appropriate follow up.  See also anaphylaxis definition.

Hospital

APLS guidelines (updated 2021) on management of acute anaphylaxis from the United Kingdom Resuscitation Council.

No distinction between anaphylactic and anaphylactoid reactions – confusing and may lead to inadequate treatment. Patients taking beta blockers may have a more severe reaction and respond less well to adrenaline.

Adrenaline is the only evidence based treatment specified in the guidelines.  It is therefore the treatment of choice.  You could argue that anaphylaxis is the one condition in which the ABC approach is not appropriate – as soon as anaphylaxis is suspected, you should give intramuscular adrenaline, and then proceed to airway, breathing etc.

Adrenaline is underused. 34% of cases of anaphylaxis in Patel’s metanalysis did not receive adrenaline (my calculation from table III); 10% needed more than 1 dose [Patel JACI 2021]. In scenario based studies, adrenaline is often not given.

Adrenaline by the intramuscular route is safe. If in doubt, just give it! Dose is 0.15mg for under 6yrs, 0.3mg for 6-12yrs, 0.5mg for over 12.  This is slightly different from the adrenaline autoinjector dose the child may have been prescribed for home use.

Repeat within five minutes if there is no improvement or if the patient’s condition deteriorates – not based on any evidence!

New guideline does not mention steroids or antihistamines at all! But does include IV bolus with second dose IM adrenaline after 5 minutes . 

Posture emphasised in new guidance – Lie down with legs raised, or allow sitting up in semi-recumbent position if that helps breathing. Beware sitting up, standing and walking even if feeling better – reported trigger for cardiac arrest – so caution when transferring.

Refractory Anaphylaxis

After that, if still not improving, there is a new Refractory anaphylaxis guideline. 

  • Get expert help.  Intravenous adrenaline should only be given by experienced practitioner.
  • Give repeated IM doses of adrenaline, or if experienced, start low dose IV adrenaline infusion:
    • 1 mg (1 mL of 1 mg/mL [1:1000]) adrenaline in
      100 mL of 0.9% sodium chloride, ie 1:100 000.
    • Beware BP cuffs and piggy back lines that will interfere and potentially cause extravasation. 
    • Start at 0.5-1ml/kg/hr and titrate.
    • Use ECG monitoring. 
  • Use nebulised adrenaline for stridor, neb salbutamol for wheeze or bronchospasm. 
  • After that intubation, inhalational anaesthetics (good for bronchospasm), repeat fluid boluses.

Discharge

Before, advice was observe for 6-12 hours, or admit if child. Now this has been risk stratified, with 6-12 hour rule applying for most cases. Exceptions are:

  • 2hr discharge if a) good response (5-10 minutes), to b) single dose adrenaline, c) given within 30 mins PLUS complete resolution PLUS already trained and with 2 unused AAIs PLUS adequate supervision
  • At least 12 hours after resolution if any of:
    • severe, needed more than 2 doses adrenaline
    • severe asthma, or had severe respiratory compromise
    • possibility of ongoing absorption eg slow release medication
    • late at night or potential to not respond to any deterioration
    • areas where emergency care difficult
  • or in context of supervised challenge

No reliable way to predict biphasic reaction so this should be discussed and decision made by senior clinician.

Follow up

See NICE guideline CG134.

Basic principles are to not discharge too soon, in case of a biphasic attack, but just as importantly, to consider prevention of further episodes (which involves making a diagnosis), and giving the patient and their family the appropriate information and skills to deal with an unexpected further allergic reaction.

Liverpool study (adults and children, I presume) found IM adrenaline given in 91.7% of cases, recommended observation period (6–12 h) achieved in 91.7% of patients. Long-term management not great – adrenaline auto-injector prescriptions provided to 50% of patients, “structured patient education” documented in 17.9% of cases, and allergy clinic referrals in 42.9%.

Who needs an Adrenaline auto-injector?

EAACI position paper suggests:

  • Absolute indications:
    • Previous cardiovascular or respiratory reaction to a food, insect sting or latex.
    • Exercise induced anaphylaxis.
    • Idiopathic anaphylaxis.
    • Child with food allergy and co-existent persistent asthma.
  • Relative indications:
    • Any reaction to small amounts of a food (e.g. airborne food allergen or contact only via skin).
    • History of only a previous mild reaction to peanut or a tree nut.
    • Remoteness of home from medical facilities.
    • Food allergic reaction in a teenager.

Prescribing a pen is only part of the overall management: nothing worse than prescribing a pen and not properly discussing avoidance, or having a pen that does not get used when it should be, because it’s left at home or because no-one remembers how to use it or they are too scared to use it.

Referral to an allergist is highlighted.  According to a Mayo Clinic study, 35% of those referred by emergency department (ED) had an alteration in the diagnosis or suspected trigger after allergy/immunology follow up.  Either anaphylaxis was ruled out; or an unknown trigger was successfully identified; or the suspected trigger was ruled out.  Allergists are also good at identifying new triggers, different from the one suspected (JACI In Practice 2014)

How well is anaphylaxis managed by emergency departments?

In 1 study from Arkansas, n=187 patients (all under 19), food (44%) and stings (22%) were the main triggers, whereas 29% had no identifiable allergen. Only 47% (n = 87) received adrenaline in the ED and only 31% of those via the preferred IM route (the rest were treated subcutaneously). 61% received autoinjectors at discharge. Only 45% received an allergy referral. [Ped Emergency Care 2016] Similar results from Birmingham, Alabama in 2010.

Most cases of anaphylaxis are coded as “allergic reaction” rather than anaphylaxis, which suggests hospital statistics are likely to represent only a minority of the cases coming to hospital. In the study above, before the 2006 NIAID anaphylaxis guidelines, only 20% of cases were accurately coded.

Anaphylaxis

Allergy, General paediatrics, Immunology

See also:

Anaphylaxis is usually defined as an acute systemic allergic reaction with compromise airways, breathing and/or circulation.  Systemic here means that the reaction is not limited to just one body system (skin, GI, respiratory etc) but spreads to others.  It is usually – but not exclusively – mediated by IgE-antibodies.

There are however 5 different international definitions – not all include systemic, and of course not all systemic are anaphylaxis (for example skin and gut, 2 systems, not usually called anaphylaxis – except 2016 NIAD/FAAD definition in US, which specifies “persistent gut symptoms”).  Respiratory involvement alone sometimes not called anaphylaxis by experts, even when treated as such! 3 definitions use “life threatening” but that is somewhat subjective and poses the danger of delaying appropriate management until the reaction is already advanced. 

Use of the word “anaphylactic” is discouraged in the Resus council guideline, unless talking about anaphylactic shock, as it is misused to describe patients at risk of anaphylaxis (they may describe themselves as such), whereas this is actually anyone with a type 1 allergy.  

Anaphylactoid reactions are immediate systemic reactions that mimic anaphylaxis but for which an IgE-mediated immune mechanism can not be established – most people don’t bother trying to make a distinction now.

Resuscitation Council definition (2021):

  • Sudden onset, rapid progression
  • Airway/breathing/circulation problems (not specified)
  • “Life threatening” includes:
    • hoarse voice, stridor
    • wheeze, work of breathing, cyanosis, fatigue
    • Signs of shock (presumably pale, clammy), low BP, confusion, reduced consciousness
    • (not tongue swelling or persistent cough)

Differential

If test unexpectedly negative, consider anergy if recent reaction. Test with raw food rather than commercial product, in case relevant protein under-represented.

Where no cause identified consider:

Rare allergens, eg galactose alpha-1,3 galactose , gelatine, pigeon tick bite (Argax reflexus), wheat-dependent exercise-induced anaphylaxis, Anisakis simplex allergy.

Differential includes mast cell disorders, asthma, panic attacks, conversion disorder, globus hystericus, vocal cord dysfunction, scombroid poisoning, vasoactive amine intolerance, carcinoid syndrome and phaeochromocytoma. 

Haemophagocytic syndromes

General paediatrics, Haem/Oncology, Immunology, Rheumatology

A group of disorders, including haemophagocytic lymphohistiocytosis, Macrophage activation syndrome, and PIMS-TS. Suspect when these unexplained or unusually severe, particularly in combination:

Prevention of peanut allergy

Allergy, General paediatrics, Immunology,

Use of peanut oil in eczema creams had OR 8 for peanut allergy but retrospective.

Filaggrin deficiency has OR 5 for food allergy, only 3 for eczema!

So could skin protection (particularly in babies with eczema) before early weaning prevent food allergy? Preliminary studies suggest 35- 50% response. Evidence that peanut consumption of household predicts peanut allergy in baby – presumably by skin sensitization.

Bamba peanut snack

Jewish children in the UK have a prevalence of peanut allergy that is 10-fold higher than that of Jewish children in Israel. This difference is not accounted for by differences in atopy, social class, genetic background, or peanut allergenicity. Israeli infants consume peanut in high quantities in the first year of life, Bamba (peanut snack, like a Wotsit) often used for weaning, so most infants have been exposed by age 12 months. [Du Toit  J Allergy Clin Immunol. 2008 Nov;122(5):984-9]

Gideon Lack at Evangelina hospital in London did LEAP study (Learning about Peanut Allergy), randomized infants with severe eczema and/or egg allergy to receive either no peanut until age 3yr, else an age-appropriate peanut snack (Bamba or smooth peanut butter, 6g) three times a week.   Among the 530 infants in the intention-to-treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (86% reduction, P<0.001). 98 participants had baseline positive SPT results, only 12% had a positive challenge so most continued the protocol.  Another 10% with SPT>4mm were excluded from the start.

Adherence to the diet was excellent.  Dust samples were taken from some participants’ beds, peanut levels were significantly higher for kids in consumption group.  There was a higher rate of urticaria in the consumption group.

IgE greater than 10 in peanut avoiding group had 100% PPV for allergy.  Peanut-specific IgG4 antibody seems to be linked to tolerance – it went up more in the consumption group, and IgG4:IgE ratio was generally lower in allergic group (most had IgG4 under 1000). [NEJM 2015; DOI: 10.1056/NEJMoa1414850]  See also LEAP-On study, which is the follow up at 72 months, still significant difference.

Michael Perkins’ EAT study of early introduction of 6 common allergens in non-high risk babies showed if strict adherence to protocol eg 2g weekly of peanut, then every case of peanut allergy could be prevented.

Risk of peanut allergy in high risk babies estimated to be about 14%. Cost benefit analysis suggests better to go for early introduction WITHOUT initial testing, as high rate of false positives. Yet in the US at least, lots of early screening happening (median number of foods tested =10!), rarely followed by oral challenge. If you tested every high risk baby in the US with IgE, it would cost $900m…

 

 

 

Advisory labels

Allergy, General paediatrics, Immunology

Or precautionary allergy labelling.

What are Precautionary allergy labels?

These are extra bits of information sometimes provided on labels, in addition to the actual ingredients.  Phrases like “May contain…”, “Made in a factory where…”.  These precautionary allergy labels are not legally required, but manufacturers are encouraged to use them to warn their customers of a risk of accidental contamination during the production process.  The Food Standards Agency  (FSA) (2006) encourages manufacturers to be as precise as possible eg which specific nut, or else peanut or “tree nuts” rather than just “nuts” but in reality different companies do different things eg Kelloggs does not differentiate between peanut and tree nuts when they put a warning label on about nuts.

Is there a real risk or not?

Contamination of chocolate is a particular problem, particularly with nuts, and with milk in the case of dark chocolate.  In some studies, half of all the chocolate tested was contaminated.

But most foods carrying such a label will not contain any of the allergen mentioned, indeed it is sometimes hard to imagine how it possibly could!  In an Irish study looking at foods labelled marked “may contain peanut/nut”, 5% had detectable peanut or nut, which is a significant proportion but actually the peanut or nut was present at such low levels they would be unlikely to cause a reaction in the majority of allergic people.

Aren’t they just a way of avoiding legal liability?

The FSA clearly state that these labels should only be used where there is a real and unavoidable risk.  And in any case, it’s not clear it changes the company’s legal responsibilities – if there is evidence that a manufacturer has been producing food in an unsafe manner, they would be liable regardless of whether there was a warning or not.

When is a trace not a trace?

The idea of threshold is important – how much of the allergen is actually present, and is it even enough to cause a reaction?  Not everyone reacts at the same threshold, and the differences between individuals can be a factor of ten or even a hundred.

In big study of peanut challenges in kids, those who got through to last stage were 13x more likely to have anaphylaxis (related to total amount of peanut consumed, presumably). Higher thresholds found in older kids, perhaps because they would have presented earlier if they had lower threshold? [PAI 2018 vol 29:754-761]

Australia and New Zealand ask manufacturers to look at actual levels of contamination before putting a warning on their products.

In the UK and Europe, the risk associated with the processes is what matters, rather than the actual levels of contamination. It’s not clear which is actually more useful.

So what should you do about traces?

Many people tend to ignore these warnings, particularly when it is something they have eaten many times before, or when it is a big brand name, and when the wording is ambiguous rather than direct.  Yet there is no good evidence that any of these things actually makes a difference to the real risk.

What is definitely true is that people have unexpected reactions and this can be after eating things marked with these warnings, but equally after eating things without these warnings.

What is also true is that allowing yourself to eat things marked with these warnings makes life much simpler!

Some patient organizations eg Anaphylaxis Campaign recommend avoiding anything marked with precautionary allergy labels, if only because this puts the control in your hands rather than leaving you at the mercy of the manufacturers.

Doctors often recommend avoiding anything with an allergy warning, because it “seems” safer and they don’t appreciate how difficult it is in day to day life.

So I think you have to make your own choice.  If you have a nut allergy, and it’s chocolate or something else that often does contain nuts eg a muesli bar, then to me the risk seems too much.  It it’s something that wouldn’t usually contain nuts, and you’ve had it before, and you’re at home with your family, then maybe the risk is acceptable to you.  But if you are away on holiday, and you’ve forgotten to bring your allergy medicines, and your asthma is playing up, and it’s late at night, then that’s probably the worst time to take a chance.    

[https://www.food.gov.uk/business-guidance/allergen-labelling-guidance-for-food-manufacturers]

Risk factors of allergy

Allergy, General paediatrics, Immunology

Children reported to have taken antibiotics during infancy (0-2yrs) were more likely to have asthma at 7.5yrs, with a dose response pattern.  No association between antibiotic use and atop on skin prick testing however!  Hoskin-Parr, Ped All Imm 2013;24:762 (Avon longitudinal study)

 

At 18/12 of age, babies born by SVD and whose parents suck their dummy are 2.5x less likely to have eczema than those born by LSCS whose parents do not suck their dummies.  Germany/Sweden, Peds 2013;131:e1829

 

Children born outside of US much less likely to have allergic disorder (OR 0.48), although those who have lived in US for 10+yrs have higher odds of eczema and hay fever cf those who have lived in US under 2 years.  But not clear whether children moved from developing or developed country.  Ped 2013;167:554

 

Inverse dose response effect between food diversity in infancy and asthma (OR 0.74).  26% reduction in asthma for every additional item of food added in the first year of life.  Increased risk of food allergy by age 6yr (OR0.7), but no longer statistically significant after excluding children with food allergy in the first year of life.  European cohort, JACI 2014;133:1056

Food allergy labelling

Allergy, General paediatrics, ,

The UK still currently follows the European Food Information For Consumers Regulation (FIR) that took effect from December 2014.

This applies to unpackaged food eg restaurants, takeaway’s deli’s, bakeries etc. It now also applies to food prepacked for direct sale (PPDS) such as a sandwich made on the premises of a cafe but wrapped (Natasha’s law).

Allergy advice boxes are no longer permitted, although “may contain” advisory labels are. The allergen should be emphasised in the ingredients panel through typeset eg font, style, colour.   The specific type of cereal or nut must also be stated.

The 14 allergens that must be highlighted under UK/European law are: cereals containing gluten (wheat, barley, rye etc), crustaceans (eg shrimp, prawn), molluscs (eg mussel, oyster), eggs, fish, peanuts, nuts, soybeans, milk, celery, mustard, sesame, lupin and sulphur dioxide at levels above 10mg/kg, or 10 mg/litre, expressed as SO2. Lupin and Molluscs added later.

There are some exceptions, where the food is so highly processed that they are no longer capable of triggering an adverse reaction eg fish gelatine in beer/wine, soya in vegetable oil.

If your allergy is not one of those listed, eg lentil, there is no legal duty for the manufacturer to highlight the presence of that ingredient, or for the restaurant to provide a full list of ingredients.  So you need to read the full list of ingredients carefully, and plead with the restaurant for details relevant to your allergy. In the past, some manufacturers highlighted allergens in a separate box, but this is no longer permitted.

The rules list nuts as:

  • almond,
  • hazelnut,
  • walnut,
  • cashew nut,
  • pecan nut,
  • Brazil nut,
  • pistachio nut,
  • macadamia nut or Queensland nut
  • and products made from these nuts.

Other types of nuts, and other foods which are not nuts (even though they are called nuts i.e. chestnuts, pine nuts and coconut), are not named in the rules, even though they are known to cause allergy in some people.

Note that by law, “cereals containing gluten” includes oats! Spelt and Kamut should be declared as containing wheat. Oats contain avenin, rather than gliadin, but related. Products containing oats that have not been contaminated by wheat can be declared “gluten free” by law, so effectively the law considers oats as both containing but not containing gluten…

See also Advisory labels.

(food.gov technical guidance on new labelling law)

There is no legal duty to highlight changes in recipes on packaging.  The same product with the same packaging can sometimes have different ingredients, depending on where it is produced.

The Food Standards Agency (FSA) has ordered councils to encourage restaurant owners to check their ingredients.

Note that non-EU countries will have their own rules eg US has only 10 ingredients that must be highlighted (not molluscs, mustard, celery, or lupin).