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Lowest Observed Adverse Effect Level

Allergy

“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 threshold dose at which you react. An eliciting dose (ED) for a specific food can then be calculated through multiple food challenges for a stated proportion of the allergic population. For example, peanut has ED 1 (where 1% of allergic population will react) of 1.3mg (1 peanut =150mg protein).

But range of reported values – type of peanut allergy? Entry criteria? Boiled or roasted? Criteria for stopping challenge?

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

Children probably more sensitive than adults (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.  But with higher threshold, and potentially delayed absorption, the reaction (when it happens) can still be severe…

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]

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]

May contain warnings

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

Levels of contamination are reported in parts per million (PPM) as it depends on how much you eat – and that then depends on the age of the person… so 5ppm is 0.5mg in 100g.

Standard portion size could be 10-100g – chocolate bar is about 20g – so 0.1mg at 5ppm. Very conservative given ED1.

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

Allergy, General paediatrics, Immunology

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

Influenza

General paediatrics, Infectious disease, Respiratory

Incubation period 1-4 days. Infectious period from day before symptoms appear, to 5 days after symptoms appear.  Virus shedding can persist for months in immunocompromised (as other viruses).

Main types A and B.  B shows antigenic drift, with minor variations over time.  A shows antigenic shift, with appearance of new N type usually associated with global pandemic eg Spanish flu. Influenza viruses circulate through birds and pigs, so new types typically occur through reassortment of genes across different species (Chinese food markets are a perfect petri dish).

Case definition

At least one of these systemic symptoms: Fever (or feverishness), malaise, headache, myalgia;

PLUS at least one of these respiratory symptoms: cough, sore throat (!), shortness of breath.

Transmission

  • Large droplet eg sneezing, range only a metre or so.
  • Direct/indirect contact eg sneezing into hands, and then to surfaces.  Survive at least 24 hrs in environment.
  • Aerosol generating procedures can produce small droplets with further range (how far?).  Includes intubation, extubation, open suctioning, CPAP/HFOV/BiPAP, CPR.  NOT high flow O2 or nebs.

Prevention is therefore by good hygiene viz covering nose and mouth during coughing/sneezing, wiping with disposable tissues, avoiding touching nose/eyes/mouth, washing hands (alcohol gel adequate if hands visibly clean); and immunisation.

For close patient contact, aprons, masks, gloves recommended.  Similarly, consider eye protection.

For aerosol generating procedures, FFP3 (filter face piece, efficiency grade 3) masks required.  Such masks can be worn for up to 8 hours if necessary.  Fluid repellent gowns if extensive secretions or bodily fluids anticipated.

Complications

  • Pneumonia, ARDS
  • Meningitis/encephalitis – see below
  • Myositis and rhabdomyolysis leading to kidney failure (esp flu B)
  • Guillain-Barre syndrome
  • Peri/myocarditis
  • Reyes syndrome (liver failure and encephalitis, also associated with aspirin)
  • Encephalitis lethargica? Probably not… Epidemic around time of Spanish influenza pandemic, fever then neuropsychiatric deterioration – estimated 1m cases globally, high mortality. Cf Subacute sclerosing panencephalitis (measles).

Encephalitis

Neurological presentations are mostly transient, improving within 48 hours. Pre-existing neurological disorders more at risk (unusually severe seizures in known epileptic children, mostly).

Rarely acute necrotizing encephalitis (treat with high dose steroids). CT can show (classically bilateral thalamic necrosis) but MRI better of course. Not just influenza but viral, and immune mediated (no virus found in brain/CSF). Familial susceptibility described due to RANBP1 mutation. [2024 Review from Toulouse]

Vaccination

See immunisation. Antigenic drift means new influenza vaccines need to be developed each year, reflecting the common serotypes affecting people in other parts of the world who have already had their winter. 

2021 metanalysis (37 studies) found immunisation in children was 53.3% effective against hospitalization (68.7% vs flu A/H1N1pdm09 specifically).

Only 44.3% for live-attenuated influenza vaccines cf 68.9% for inactivated vaccines.

2017 metanalysis: similar effectiveness vs asthma ED visits.

Long list of people at higher risk eg chronic cardiac/respiratory conditions.  Includes pregnant women.  See Green book on immunizations.

Nasal (live) and injectable (inactivated) vaccines available.

Treatment

See Influenza treatment.

Hyperhidrosis

Dermatology, General paediatrics

= excessive sweating.

Primary usually develops in adolescence, usually focal esp palms, soles, axillae.  Often family history.

Secondary tends to be generalized but can be focal.  Long list of causes – endocrine, neurological, chronic infection, catecholamines etc.

Treatment in children is limited to anti-perspirants and iontophoresis devices (these would have to be purchased by the family – there are tray devices for feet and hands, or pads for the body, you use 3 times a week).

For the armpits you can use aluminium hydrochloride (eg Driclor). It can cause irritation so you need to dry the armpit carefully before use (a blow dryer can be good for this).

You may sometimes need topical steroid if the skin gets very inflamed.

I believe GPs can prescribe 1% glycopyrrolate in cetomacrogol cream for use 2-4 times daily.

For widespread sweating, you can prescribe probanthine or oxybutinin as you would for adults – build up the dose slowly to avoid side effects. Clearly surgery (sympathectomy) and botox are a last resort, and you would need to find a provider happy to offer this to a young person under 14. 

Patient Support

Patient Support is available at www.sweathelp.org (US) and https://hyperhidrosisuk.org/ (UK).

Young person site http://www.sweatometer appears to be down.

Murmurs

Cardiology, Clinical, Common, General paediatrics

An added sound heard when listening with a stethoscope, distinct from heart sounds or other clicks or snaps.

Can indicate a structural abnormality.  But can be heard in normal hearts too, esp kids.

Still’s murmur

Or “innocent” murmur.  Characteristic vibratory, low pitched, crescendo-decrescendo sound – “like an Aeolian harp” – loudest along left sternal border.  Never louder than grade 3.  Typically gets quieter when child sits or stands up (reduced venous return?) – you would not expect a murmur caused by a structural abnormality to change much.

Present at any age. Usually goes away by adolescence.

Venous hum

Another innocent one, a rumble heard in the upper chest, disappears when lying down, or when neck turned or neck veins occluded gently.

Pulmonary flow murmur

Pulmonary valve closest to anterior chest wall, which might explain why you sometimes hear this.  Might be confused with pulmonary stenosis or subaortic membrane.

Prolonged QT interval

Cardiology, General paediatrics

An abnormal finding on ECG.

QT interval changes with heart rate, so usually calculated as corrected QT (QTc), where average QT is divided by square root of RR interval (ie 1 second, if heart rate 60).

Associated with dysrhythmia, especially torsades de pointes (polymorphic ventricular tachycardia).

Seen with:

  • Genetic predisposition – Long QT syndrome
  • Certain drugs – antipsychotics (eg chlorpromazine, quetiapine), antiarrhythmics (!?), tricyclic antidepressants (eg amitriptyline), other antidepressants (eg citalopram, venlafaxine), antihistamines (terfenadine, but also loratadine, diphenhydramine, astemizole), macrolides, quinine.

Roseola

Clinical, Dermatology, General paediatrics

Or erythema subitum, or Sixth disease.  Dramatic viral rash.  Caused by Herpesvirus 6 and 7.

Classically high fever, URTI symptoms or no focus, potentially febrile convulsion!  Then rash appears as fever subsides, day 2-4.

Rash is widespread fine maculopapular, can be pale haloes around spots, mostly on trunk.  Can be in mouth!  Not itchy.

Pityriasis rosea

Clinical, Dermatology, General paediatrics

A viral rash, sometimes dramatic, can last for months!  Typically young adults. Some characteristic features:

  • Viral illness itself can be trivial
  • Usually not itchy
  • Herald patch – starts with an oval scaly macule, can grow up to 5cm in diameter. Looks like ringworm, but then:
  • Then multiple smaller scaly oval macules or plaques, typically chest and back – up to 20 days after appearance of herald patch. Classically “pine tree” distribution –  think drooping branches extending out from midline.

Sedation

General paediatrics

[NICE guideline]

Ensure that healthcare professional and assistant available and trained, with resus and monitoring equipment available.  Should have a record of practical experience of sedation under supervision, WBAs etc.

Document informed consent.

Confirm time of last food and fluid – fasting not required for minimal sedation eg nitrous oxide, or where child will maintain verbal contact.  Else 2-4-6 fasting rule.

Prepare child and  family psychologically.

For painless procedure eg imaging, use choral (under 15kg), midazolam.  For painful procedures, use nitrous oxide, oral/IN midazolam +/- local anaesthetic.

If unsuitable, ketamine or IV midazolam (+/- fentanyl) – combination of opioid and ketamine requires anaesthetic training.

[http://www.nice.org.uk/guidance/CG112/chapter/1-Guidance]

Antihistamines

Allergy, General paediatrics, Immunology

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]