Category Archives: Immunology

Mustard allergy

One of the 14 ingredients that must be highlighted on EU food labels.

Probably more common in France, not much data for UK but seems rare.

One of the spices that has cross reactivity with mugwort so look for other foods causing problems, as in celery spice mugwort syndrome.

Used in lots of different cuisines across the world eg black mustard seeds in curry, not just mustard as used on hot dogs and sandwiches. Also a key ingredient in:

  • mayonnaise (more usually the egg causes problems but could be either or both),
  • ready meals and other prepared foods,
  • Salad dressings,
  • Honey and mustard sauce eg for chicken, gammon,
  • Chutneys,
  • Pickles eg gherkins

Sometimes mustard leaf gets used as a vegetable!

Nightshade family

Vast group of vegetables. As with all cross reactivity, allergy is not automatic but being allergic to one or more increases the chance you will be allergic to another.

  • Tomato – but see also salicylate intolerance
  • Aubergine – can contain histamine like chemicals!
  • Bell pepper (capsicum) – from which you get the spice paprika, often used in other things eg salami, pepperoni
  • Chilli pepper
  • Potato (but not sweet potato). Raw potato is sometimes the problem (contact, obviously) rather than cooked.

Vaccine allergy

The most common adverse events of vaccines are fever, local pain or irritation, and local redness or swelling, which are not signs of allergy

With live vaccines, adverse effects can be delayed until 7 to 21 days after immunization; this includes vaccine-induced delayed-onset urticaria, which is commonly mistaken for allergy.

Assessment and allergy-focused clinical history

  • Testing appropriate for all, whether anaphylaxis, mild symptoms, unknown history or family history.
  • Gold standard is an oral challenge with a therapeutic dose of amoxicillin, 1hr observation, then 5 day course at home to ensure no delayed reaction.
  • Low risk individuals, where IgE mediated reaction unlikely, can go direct to challenge without testing.
  • Puncture and intradermal skin testing is recommended where reaction was within last 12 months, or there were respiratory symptoms. 
  • Skin testing using only penicilloyl-polylysine, with at least 5 mm of wheal and flare greater than wheal as the criteria for a positive test result, is now sufficient to rule out a high risk of having anaphylaxis during a confirmatory oral amoxicillin challenge

Egg is used in the manufacture of a number of vaccines. Whether this is clinically significant or not depends on the vaccine and the severity of the allergy:

  • MMR – only contraindication is anaphylaxis to MMR or other constituent of MMR vaccine
  • Influenza – (live nasal or inactivated injectable) patients with “severe anaphylaxis” (ie requiring intensive care) should be vaccinated in hospital.
  • Varicella, Rabies – no contraindication for egg allergy
  • Yellow fever – discuss with specialist if egg allergy

Gelatine (derived from pork or beef) can be a cause of allergic reactions esp MMR, Varicella, Japanese encephalitis. Allergy would usually be established from history of food reactions eg gummy/jelly sweets, marshmallows.

Latex – can be present in syringe or bung. See Latex allergy.

Despite these potential causes of allergy, immunisation can often be achieved through graded administration.

Some reports of persistent itchy nodules at injection site due to aluminium delayed hypersensitivity.

https://www.annallergy.org/article/S1081-1206(18)30627-6/fulltext#/article/S1081-1206(18)31201-8/abstract

Fruit allergy

A range of possibilities!

  • Isolated type 1 allergy
  • Multiple type 1 fruit allergies – usually to similar fruit but also some common co-sensitivities eg banana/melon/avocado/chestnut/latex group
  • Oral allergy syndrome (pollen food syndrome) – esp peach and related stoned fruit, cross reactivity with pollen (so hay fever), sometimes nuts too. Various patterns depending on allergen family.
  • Salicylate intolerance (so not allergy) esp cherries, raw tomato, pineapple juice
  • Histamine-releasing foods (wine famously, otherwise strawberry, papaya, kiwi and pineapple)
  • Naturally occurring serotonin (tomato again, banana) and tryptamine (tomato again, plum) cause allergy like symptoms [EAACI 2023]

Berry allergy

Some evidence of cross reactivity between raspberry and strawberry but there’s not much evidence to suggest cross reactivity with other berries.  There’s a theoretical link with blackberry, and other things in the same family (Rosaceae – massive group of fruit including apples, peach, pear, apricot, cherry).

Only one report of blueberry allergy ever!

Found one paper that said tree nuts, celery and parsley might also be related to berries, but again I think theoretical.

Pineapple allergy

Can be part of pollen food syndrome (due to profilin allergy) so mostly oral symptoms, hay fever, cross reactivity with other fruits as well as nuts.

Might be salicylates as above rather than allergy.

But can also be allergy to bromelain (similar to papain), with potential for anaphylaxis.

Sometimes associated with latex-fruit syndrome and ficus-fruit syndrome (all tropical, not latex – kiwi, papaya, avocado, banana).

Melon allergy

Can be part of banana/latex group, but also cucurbitae – watermelon, cucumber, courgette, pumpkin.

Salicylate intolerance

Can cause allergy like symptoms eg wheezing, itching, swelling, nasal congestion. Also headaches, abdo pain. Anaphylaxis reported.

Found in foods, medicines, beauty products.

High levels:

  • Cherries and strawberries, tomato (raw)
  • Ginger, mustard, curry powder (?) 
  • Liquorice and mint

Pineapple juice high but fruit itself not listed!?

Medium:

  • Black pepper
  • Sweetcorn
  • Fizzy drinks
  • Ketchup, Worcestershire sauce
  • Honey


Benzoates related.  A variety of other foods esp fruits but also avocado, vegetables, nuts, coffee, beer too.

Management

If suspected, exclude high salicylate foods only to begin with, and limit medium salicylate foods if possible.  4/52 minimum.  Includes topical including anything with “Natural plant extracts”. 

If improves, excluded medium too for further 2/52 to see if additional benefit. 

(draft BDA FAISG)

Lowest Observed Adverse Effect Level

“Highly allergic” or “severely allergic” can mean low threshold for reacting, or severe previous reaction, or both!

Lowest observed adverse effect level is the formal term for the minimum dose at which you react! An eliciting dose (ED) can then be calculated through multiple food challenges for a stated proportion of the allergic population. For example, 1 peanut =150mg protein. ED 1 (where 1% of allergic population will react) is 1.3mg. But range of reported values – type of peanut allergy? Entry criteria? Boiled or roasted? Criteria for stopping challenge?

Higher eliciting dose predicts future tolerance, at least for milk and peanut, maybe not for egg.

Children probably more sensitive although ED 10 similar for children and adults.

Conflicting evidence on severity of reaction vs threshold.  Certainly trace amounts can cause anaphylaxis in some cases.  Higher fat content delays absorption, so the reaction (when it happens) can still be severe…

ED05 of 1.5mg for peanut seems safe [Hourihane].

Being cross allergic to other things might help predict – in French study, 3 phenotypes emerged from cluster analysis:

  • Cluster 1 have high level of rAra h 2 (mean 81), low threshold reactive doses for peanut and high proportion of asthma;
    • Cluster 2 (mostly boys), have high threshold, milder symptoms, and the lowest proportion of asthma/AR and cross-allergy to TN and/or legumes;
  • Cluster 3 have low Ara h 2, high risk of cross-allergy to TN and/or legumes, and most patients suffer from eczema.  [Matthias Cousin, Lille, PAI]

Complicated though – thresholds vary up to 10x for individuals in sequential challenges (n=14)!

On the day factors – alcohol/meds, infection.  Exercise is a factor in 15-20% of anaphylaxis episodes according to German/Austrian registries.

TRACE peanut study – 45% reduction in threshold for exercise and sleep deprivation (independent) esp at lower eliciting doses. ED1 and ED5 remain above 0.2 though.

Sleep deprivation (sleep overs!) worsened severity of reactions too, by 48% – exercise 28%, not significant. Repeated challenges also seemed to increase severity. [score for severity using Practall criteria. JACI 2022 Dua]

Lower thresholds had higher BAT and SPT – 8mm cut off had 100% sensitivity and NPV for severe reactions, and 92% specificity. Has nomogram combining all tests! SPT 6mm had 92% sensitivity, 95% specificity and 100% NPV for low threshold.  [JACI 2020, Santos study – LEAP cohort]

Particulate contamination risk seems to be a particular problem for milk in chocolate – big range of values found cf peanut.

UK and Europe look at processes as the way to assess risk of contamination with allergens. But not consistent between countries of the EU, let alone globally.

Quantitative methods would  appear to make sense – how much allergen is actually present in a given sample? But of course one sample may differ from another (“particulate contamination”).  Also difficult to establish minimum eliciting or threshold dose (consider denaturation of the allergen during processing, derived ingredients eg glucose syrup from wheat, soya lecithin, effect of food matrix, individual factors). 

Australia and NZ use lowest observable adverse event level (LOAEL) already – warnings required within 10x concentration of LOAEL (“VITAL” threshold, as in toxicology).  Studies from Europe and US have found most advisory warnings used for ingredients below the VITAL threshold.

But then it depends on how much you eat, as well as presence of other co-factors that are known to contribute to risk of anaphylaxis.

[BMJ 2011;343:830][Allergy 2021, Paul Turner]

Coconut allergy

Not a true nut (along with chestnut, pine nut, tiger nut, doughnut etc), classified as a fruit, from palm family. Allergy is pretty rare, but is possible, usually only seen in people with other allergies.  Associated with macadamia, almond, walnut, hazelnut, lentil and latex allergy.

The major allergens are storage proteins (7s globulin=vicillin like), so not affected by heat.

In EU, does not have to be specifically highlighted on labels, but in US FDA do include it under nuts!

Other names , particularly when used in cosmetics:

Cocos, cocamide sulphate, cocamide DEA, CDEA, Cocamidopropyl betaine.

People who react when they eat coconut don’t necessarily have a problem with it on their skin, but this may depend on whether they have eczema.  Where people do react to skin products, complicated, because one of the intermediates in manufacturing (found at very low level) appears to be a more likely cause of type 1 reactions than coconut itself or one of the listed coconut derivatives.

Contact dermatitis triggered by coconut much more common than type 1 allergy.

Sources of coconut:

  • Fruit smoothies
  • Snowball type sweets
  • Bounty chocolate bars and similar
  • Indian or other Asian sweets
  • Some flavoured rums eg Malibu, and cocktails eg Pina Colada

Antihistamines

First generation have prominent CNS effects, usually drowsiness (which an be useful, eg to help sleep in chronic itch) but can be hyperactivity, paradoxically!

  • Ketotifen – age 3+ only. Sugar free 300ml bottle (Zaditen) is only £17. Give with food. 1mg per 5ml, dose is 1mg twice daily from age 3 so 250 (1.25ml)-500 (2.5ml) mcg below that?
  • Promethazine hydrochloride (have to specify HCl as also comes as teoclate) 2+ for allergy but 1/12+ for sedation! Unlicensed for sedation! Phenergan 100ml sugar free £4.
  • Hydroxyzine 6/12 and over, but special order only. Risk of long QT.
  • Alimemazine – BNFc gives dose from 6 months (specialist use only and unlicensed until 2). Solution is minimum £89 a small bottle and often higher.

Second generation have lower incidence of these side effects. BSACI peanut and tree nut guidance specifies “long acting antihistamines with rapid action eg cetirizine”. Resus council anaphylaxis guideline says “non-sedating oral antihistamines in preference to chlorphenamine” may be given following initial stabilisation.

Benadryl (brand name) can be either cetirizine or acrivastine.  Latter marketed as “fastest acting allergy capsule” – I suspect the only allergy capsule.

Tmax (plasma) lowest for Rupatadine (0.75hr), levocetirizine (0.8), cetirizine (1).  Chlorphenamine is 2.8, worse than diphenhydramine (best of the sedating antihistamines at 1.7).  Loratadine (1.2) and Acrivastine (1.4) not far behind; Desloratadine has a range of values from 1-3, which is unhelpful, Fexo is definitely slow at 2.6.

In terms of clinical effect on wheal (because tissue distribution different from plasma), cetirizine, acrivastine, levocetirizine equivalent (1hr), diphenhydramine, fexo, desloratadin 2 hrs, CPM 3hrs (!).  Rupatadine is 2 hrs, despite the short Tmax!

No particular reason to think formulation matters. Possibly liquid might work directly in the mouth and throat, but only if you don’t swallow it immediately (gargle!?).

Some examples of capsules beating liquids for specific drugs (!?) but prob not much difference between absorption from tablet, liquid etc. Prob easier to swallow liquid if oral angioedema, but liquid bolus might actually be harder than tiny tablet…

[J Investig Allergol Clin Immunol 2006; Vol. 16, Supplement 1: 3-12]

Egg allergy

Common.  Associated with eczema.  Can be prevented by early introduction as part of weaning – see EAT study, where 75% of cases prevented where families could stick to protocol.

Mostly mild reaction, 7% anaphylaxis quoted before diagnosis made.  Moderate to severe reactions can occur just from contact, if raw egg has been applied to inflamed nappy rash.

Diagnosis is made clinically.  No investigations are required if reactions mild (not really defined!).  Testing “useful” in “mod-severe” reactions (not specified really but does say hospital challenge if “severe vomiting or diarrhoea”).  No cut off given for SPT or IgE although historically 95% PPV at 4mm or 4ku/l under age 2, 7mm or 7ku/l over the age of 2. 

Encourage early introduction of peanut (do peanut test at the same time, if you are going to test), as per EAT study. 

Children referred to dieticians have half the rate of accidental reactions! Referral to dietician if multiple food allergies, or nutritional concerns, or difficulty following ladder; or if severe allergy. 

1/3 of children grow out of their egg allergy by age 3, 2/3 by age 6.  Predictors of tolerance are ability to have baked egg, mild reactions only, isolated egg allergy, IgE level (and presumably SPT but not mentioned).

Predicting tolerance of cooked egg tricky – Gal d1 (ovomucoid component – heat stable) >=11 indicated high risk of reacting to cooked or raw [NOT baked?]. Also linked to persistence of egg allergy. In 1 study, helps predict tolerance of boiled egg, whereas Gal d2 (ovalbumin – heat labile) predicts tolerance of raw egg. If isolated Gal d2 positive then likely transient. Better predictive value than regular IgE for egg anaphylaxis. Can be useful for assessment of resolution in adults.

Ovomucoid sIgE ≤1.2 kUA/L considered safe for home introduction.

In study of raw egg tolerance at age 5+, ovalbumin IgE/total IgE ratio was best predictor.

Since most children do grow out of this allergy, step by step, cautious reintroduction should be encouraged from 12 months of age, or 6 months after the last reaction.  This can be safely done at home unless:

  • history of severe reaction
  • severe or poorly controlled asthma

Mild asthma, and reaction to trace amount (or contact only) are relative indications.

For severe allergy, or allergy beyond age 6-7yrs, check history of reactions and repeat tests – but no specific IgE levels to indicate when to challenge! “Reasonable” if no recent reaction and reduction in IgE or SPT.

Egg “ladder” for step by step reintroduction simply baked egg (eg sponge cake), followed by less well cooked egg (French toast), followed by raw or nearly raw (mayonnaise). 

Where stage 1 achieved but difficultly moving further, regular ingestion should promote tolerance

Although can be frightening to challenge at home, prolonged total exclusion more likely to lead to persistent allergy, and of course increases dietary plus social exclusion. 

If there is a reaction at any stage, the previously tolerated diet should be continued and further escalation considered after 3-6 months.

Taste can be an issue – try egg fried rice, or sweet muffin, egg noodles, Quorn, sponge fingers, egg custard.

Remember vaccines – MMR made using egg but no identifiable egg protein remains so egg allergy not given as possible contraindication.  Out of the scheduled vaccines, only influenza vaccines is a potential issue, and even then nasal flu vaccine (or low egg or egg free injectable version) can be given with standard precautions unless anaphylaxis to egg requiring intensive care. Just specialist travel vaccines eg Yellow fever that might be an issue. For latter, should be “referred to specialist with access to designated YF vaccination centre” (3 in Lanarkshire, including Monklands hospital travel clinic and Calderlea centre at Alison Lea!).  No mention of JE, TBE??

[BSACI guidance 2021]

Egg allergy in adulthood has significant impact on quality of life, particularly around dietary restrictions and emotional impact. “Bird-egg syndrome” is allergy to both egg, feathers and chicken, due to Gal d5 (alpha livetin) sensitisation – can develop in adulthood, usually where exposed to feathers.

Treatment

No standard immunotherapy regime for egg. EAACI do not recommend OIT for persistent egg allergy.

One regimen is with raw egg white powder (!), aiming for target maintenance dose of 1g of egg white protein (approximately 1/3rd of an egg white). If no success, switch to cooked egg and try again. 3 months after reaching target dose, oral egg challenge with half a boiled egg white – if passed, allow up to one-half of an egg in heated form, but do not increase amount of raw egg. Aim for continuous daily consumption and add well cooked egg (eg meatballs, egg pasta, brioche bread, pancakes, pastries) into the diet.

Cochrane review 2018 (10 RCTs, ages 1-18), 82% achieved 10g egg protein (1 egg) cf 10% of control. 50% achieved sustained unresponsiveness by the fourth year. Small studies, low quality evidence.

In 2021 Helsinki study, after 8 months of OIT, 44% of the children were desensitized, 46% partially desensitized; at 18 months, over 80% eating egg regularly, 72% able to eat target dose. More than half not restricting at all. 

Early discontinuation is associated with underlying asthma, higher specific IgE and lower threshold during challenge.

Ovomucoid (Gal d1) IgE 8.85 kU/L indicated a 95% probability of early discontinuation or ongoing reactions over time. Ovalbumin (Gal d2) is heat labile so if this is the only one you are sensitised to, you should be ok with baked.

Low pre-treatment levels of egg white and ovomucoid IgE predict sustained unresponsiveness following egg immunotherapy. Decrease in size of SPT and increase in egg-specific IgG4 over time predicts tolerance in children being treated with egg OIT. Ovalbumin IgG4 and Ovalbumin IgE/IgG4 ratio may be useful to predict the development of tolerance to egg in oral immunotherapy.

High egg IgE levels and sensitization to all four components (Gal d 1-4) predicted failure or impaired response, but Helsinki authors still felt OIT worth trying.

Another way would be to start with egg yolk (carefully separated and the sac disposed of, since it has been in contact with the white) – discussed in a Japanese paper looking at a single adult female – or even quail egg followed by duck egg (TIP style programme).

Rheumatic fever

Rare in developed world now, still common in underdeveloped world, or at least in underdeveloped communities eg Aboriginal Australians.  Prob also genetic susceptibility.

Caused by Group A streptococcus.  Important cause of acquired heart valve disease.  Can recur.

Probably cross reactivity between specific Group A strep M proteins and human tissues.

Erythema marginatum
Erythema marginatum

Diagnosis

Jones criteria:

  • Major
    • Carditis eg new murmur.  Mitral most commonly, classically apical blowing pan-systolic.  Aortic next most common.
    • Arthritis esp large joints.  Migratory.
    • Subcutaneous nodules – these are the most uncommon major criterium (in Turkish study of over 1000 cases there were none with nodules).  Typically over extensor surfaces of joints, 0.5-2cm, symmetrical.
    • Sydenhams chorea
    • Erythema marginatum – not specific to rheumatic fever. Seen in 0.4% of Turkish study patients. Serpiginous or annual eruption, can look similar to erythema multiforme. Provoked by warmth eg bath.  Non pruritic.
  • Minor
    • Fever
    • Arthralgia
    • Prolonged PR interval on ECG
    • Elevated CRP/ESR
  • 2 major or 1 major plus 2 minor, plus confirmation of group A streptococcal infection eg positive culture, high ASO titre sufficient for diagnosis. Modified Jones takes into account background incidence.

Note that initial infection may be subclinical eg pharyngitis, erysipelas. Symptoms of rheumatic fever develop 10 days to several weeks later. Chorea can appear months later.  Low threshold for echo as carditis can also be subclinical.

Established criteria for rheumatic valvulitis – Gewitz 2015

Treatment

Antibiotics – Treat with penicillin,  this does not however affect clinical course but hopefully prevents further spread of that particular bug. Traditionally single dose intramuscular Penicillin G Benzathine.

NSAIDs for joint pain.  Usually dramatic response, if not then reconsider diagnosis!

Valproate for chorea, possibly steroids – see Sydenham’s.

Aspirin and/or Steroids for carditis, but not much evidence.  Diuretics, ACE inhibitors for cardiac failure.

Long term treatment

Recurrence with progression of valve damage is the main concern, and well recognized. Subclinical carditis improves in about 50% but definite risk of progression (mild definite and borderline RHD showed 26% and 9.8% echocardiographic progression respectively).

Regular intramuscular penicillin (benzathine pencillin G) every 2-3 weeks has the lowest recurrence rates but oral penicillin V more acceptable.  Erythromycin or cephalexin if allergic.

WHO recommendations:

  • Rheumatic fever without carditis: 5 years after last attack or until age 18 (whichever is longer)
  • Rheumatic fever with carditis but without residual disease: 10 years after last attack or until age 25 (whichever is longer)
  • Residual valve disease or valve replacement: lifelong

American and Australian heart association guidelines vary slightly:

Penicillin prophylaxis guidelines comparison