Refractory iron-deficiency anaemia is not considered a good reason for testing anymore.
Gold standard is Gastric biopsies (antrum and corpus) for histopathology during endoscopy. Initial diagnosis of H. pylori infection can be based on either positive histopathology + positive rapid urease test, or a positive culture.
Stool antigen test is pretty reliable. Could simply indicate asymptomatic carriage though. Once you know about it, of course, you need to consider eradication given cancer risk.
You should wait at least 2 weeks after stopping proton pump inhibitor (PPI) therapy and 4 weeks after stopping antibiotics before doing any of these tests.
Detection of antibodies against H. pylori (whether in blood, urine, saliva) are not reliable for use in the clinical setting.
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.
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.
In various studies, prescribed AAIs were only used in a third of recurrent episodes, despite being available and in date in two-thirds of episodes. The reason(s) for non-use requires further study: parental questionnaires indicate that parents have a poor recall of anaphylactic symptoms and how to use the AAI despite training.
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).
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)
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…
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?
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 minsPLUS 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.
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.
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 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.
EAACI task force anaphylaxis criteria (2007, from Sampson): any one of –
acute onset (up to several hours) skin/mucosa reaction (eg generalized hives, pruritus or flushing, swollen lips/tongue/uvula) plus respiratory or cardiovascular compromise eg dyspnoea, bronchospasm, stridor, hypoxia, hypotension, collapse
acute onset after exposure to likely allergen of at least 2 of: skin/mucosa changes, resp, cardio compromise, persistent GI (eg crampy abdo pain, vomiting)
hypotension after exposure to known allergen for that individual
Note that this definition talks about “compromise”, and the examples given are mostly signs that only a medical professional could identify! This doesn’t help patients/parents. It also allows for anaphylaxis with just skin and persistent GI symptoms (where likely allergen exposure).
In Sampson’s original 2003 criteria, he grades anaphylaxis into 5 types. 1 and 2 would not be considered anaphylaxis these days at all!
WAO 2020 revised definition, based on input from 15 different allergy societies – “highly likely when any 1 of
acute onset skin/mucosa plus one of airway/breathing compromise, circulation, severe GI, or
acute hypotension, laryngeal involvement, bronchospasm [specifically] after likely exposure, even without skin symptoms.
BSACI’s allergy plan includes as severe symptoms hoarseness, dysphagia but also:
AAP also has cough, hoarse, PLUS severe vomiting and diarrhoea, “many hives”(!), agitation!
On logistic regression, confusion and incontinence were strongly associated with hypotension and hypoxia. Dizziness, vomiting, abdominal pain, dyspnea and chest/throat tightness had weaker, albeit significant, associations. Pre-existing lung disease was associated with an increased risk of hypoxia. [Journal of Allergy and Clinical Immunology Volume 114, 2004, 371-376]
In a survey of kids with anaphylaxis, the mean latent period was 15.4 (SD27.5) minutes, ie 95% will react within 90 minutes of exposure. The type of allergy does not predict the latency well; however, age is inversely related, with younger children having more gradual onset. GI and cardiovascular symptoms tended to come later than skin/respiratory. 60% of anaphylactic reactions occurred in the home, and 10% happened in health care environments. Males predominate, particularly with regards exercise induced and insect venom anaphylaxis [PEDIATRICS Vol. 101 No. 4 April 1998].
Biphasic anaphylaxis
About 20% to 30% of food-induced anaphylactic events have a biphasic or recurrent response, although only half of those severe. 90% of recurrent reactions within 12 hours. Delay in giving adrenaline increases risk of recurrence! Some anaphylactic reactions are persistent, going on for hours.
Recognition
Recognition of anaphylaxis can be poor by non-experts. It is sometimes assumed that anaphylaxis must be life threatening, and that it must be progressive to the point of shock/collapse. Well recognised that anaphylaxis can resolve without treatment in some cases. Some have called for anaphylaxis grading, such as Sampson’s, but this then undermines the basic distinction.
Equally, people will sometimes diagnosis anaphylaxis on the basis of severe facial swelling, or widespread rash, neither of which are criteria.
Part of the problem of course is that what parents report is not the medical terminology included under the definitions. Infants and toddlers are a particular problem, since they cannot describe what they feel, and hypotension/syncope are extremely late signs. In US study, 48% of caregivers recognized 1 or more less obvious symptoms of anaphylaxis only in retrospect [but that includes skin/tongue/GI symptoms: looking at table II, 15% recognised sudden behaviour change in retrospect, 11% cough/wheeze, 6% wobbly/lethargy, difficult to rouse – can’t add up though]– that lack of recognition may affect management by medical team.
US 2024 study (Handorf) proposes modified NIAID/FAAN criteria – swollen tongue/uvula/pharynx becomes respiratory, not mucocutaneous; adds cough, drooling, hoarse cry/voice to respiratory too; specifies gagging, spitting up, diarrhoea, back arching as GI; pallor, mottling, obtunded/lethargy, altered mental state as CVS. By these criteria, 52% of all ED visits in children under 5 then became “anaphylaxis” (includes those given that diagnosis by attendings plus some ambiguous cases determined by clinicians to be anaphylaxis). Attendings diagnosed anaphylaxis in 68% of cases, but falls to 59% in infants. Original NIAD/FAAN criteria have 85% sensitivity, but falls to 77% infants. Modified criteria 100% sensitive for infants; 96-98% of older children. Compared with NIAD/FAAN, modified criteria picked up 43% more CVS signs, and 32% respiratory. Only 5% increase in GI. No hypotension/syncope in infants/toddlers, as expected.
Epidemiology
UK hospital admissions for food anaphylaxis have increased by 6.6% each year between 1998 and 2018 for under 15s (about 3x increase over whole period). For other ages much lower increase. Possibly due to 4hr waiting time rules for emergency departments? Or NICE recommendation on observation after suspected anaphylaxis? Case fatality rate has gradually fallen over time. At least 46% of all deaths triggered by peanuts or tree nuts. Cow’s milk responsible for 26% of deaths in school aged children (and rising), which shows how serious it can be when you don’t grow out of it in infancy. About a quarter trigger unknown (no comment – presumably no details in coding, rather than actually unknown), peanut and tree nuts together about a third. AAI prescriptions over the same period have increased by 336%.
Commentary by authors talks about effects on family of food allergy diagnosis but then goes straight into reasons for overdiagnosis, either through self reporting, commercial pressures, even campaigning by allergy charities. They say it is a “familiar pattern” with sharp increases in softer indicators of allergy, but no increase in markers of severe disease, and that this is the case in other countries such as the US and Australia. They conclude that we live in an era of increasing concern and awareness, but not a food allergy epidemic.
Whether the data are reliable, is a whole other question. Anaphylaxis is not well recognized, treated or documented, and only cases that were admitted were included, so these cases are probably just a fraction of what is actually coming to emergency departments. That doesn’t matter so much if that fraction stays the same and you’re only interested in trends. But even the interpretation of their own data seems curiously sceptical – if it is true that allergy is no more common than it was at any time in the last 30 years, are we saying families in the past just didn’t bother bringing their children to hospital when they had anaphylaxis? Or just more likely to admit (as NICE guidance from 2011 encourages observation for at least 6 hours, although the authors themselves say this probably only produced a minor increase in cases)?
Falling rates in peanut/nut, better awareness esp industry? Whereas milk awareness low? Although milk allergy common in young children, 5% of deaths in adults still due to milk (and prob harder to spot than nuts in food).
Higher rates of food anaphylaxis admissions in boys before puberty (male-to-female ratio 1.6:1), but reverses from age 15 years onwards. Highest rates of admission and death in teenagers, but in this study this risk continues through into mid adulthood, so supports the idea that it’s not specifically “teenage behaviour” that increases risk, rather biological vulnerability. In children under 5, deaths rare even though highest rate of admission.
Fatal anaphylaxis rate is about 1 in ¼ million. Risk of hospital admission with anaphylaxis 1 in 10 000. More likely to die on way to hospital appointment!? Doesn’t mean we avoid driving. Important to see that there can be an “acceptable risk” of living with food allergy.
Although there are a range of associations, most of these are very weak, which makes them unhelpful, or even misleading.
There is also a difference between sensitivity and severity. Some children during food challenges may only start reacting after a relatively high threshold dose – but their reactions tend to be worse, not unexpectedly.
Exercise is an important factor esp in teenagers, can even (rarely) be the sole identifiable trigger! See Exercise-Induced Anaphylaxis.
Statistically, females have worse reactions. In mice, the difference appears to be due to effect of oestradiol on increased tissue expression of eNOS (one of the NO synthases).
Medication – eg beta blockers, NSAIDS may increase risk.
Sleep deprivation reduced threshold in UK TRACE peanut study!
Most food anaphylaxis related to nuts (including peanut) and milk, but this is partly just how frequent these allergies are and how frequently the foods are encountered.
Deaths
Mostly in children over 5, despite the fact that food allergies are more common under 5 and usually lessen with time. Families often assume risk is higher in young children, which is incorrect. Nearly all are in children with asthma. Of the 8 deaths between 1990 and 2000, 4 were due to milk, 2 peanut, 1 egg and 1 mixed (but see below for bigger study). Both the peanut deaths were in children over 13yrs. Children are over 250x more likely to die in road traffic accident, although this is hardly a fair comparison.
Fatal Anaphylaxis Registry – set up in 1994 by Dr Richard Pumphrey based at Manchester University NHS Foundation Trust. This is now evolving into a European wide anaphylaxis registry.
In 80% of fatal anaphylaxis cases [mixed causes], adrenaline not given before arrest, which suggests delayed administration could be a factor. Same study shows that adrenaline does not prevent death even when given before arrest.
Most cases were in people with no previous history of anaphylaxis [but how many nut+asthma, where higher risk recognised?]
Survival better if adrenaline given within 30 mins [1992 Sampson article NEJM].
1 death at 6 hours, despite repeated adrenaline. 1 death after intentional consumption, despite immediate epipen administration.
So avoidance and asthma management are arguably more important than providing adrenaline autoinjectors! [Pumphrey]
Differential
If test unexpectedly negative, consider anergy if recent reaction. Test with raw food rather than commercial product, in case relevant protein under-represented.
A group of disorders, including haemophagocytic lymphohistiocytosis, Macrophage activation syndrome, and PIMS-TS. Suspect when these unexplained or unusually severe, particularly in combination:
persistent or intermittent fever
elevated or rising ferritin or other inflammatory markers (CRP, LDH)
splenomegaly (eventually hepatosplenomegaly)
inappropriately low or falling haemoglobin, platelets or white cells (neutrophils and lymphocytes) -evolving into severe pancytopenia
coagulation abnormalities (in particular, hypofibrinogenemia, increased D-dimers, even DIC)
hepatic dysfunction including high triglycerides
CNS dysfunction (including seizures and encephalopathy, with raised CSF protein)
The underlying problem is the inability to kill infected target cells. The frustrated NK-l and cytotoxic T-cell activity leads to a massive inflammatory cascade, resulting in macrophage activation, dissemination, and organ infiltration. The haemophagocytosis of the name refers to characteristic macrophage/histiocyte consumption of erythrocytes, most evident in the marrow but sometimes seen in the peripheral blood film. Not always dramatic, not always evident at presentation so serial bone marrow examinations may be required (spleen aspirate?).
There are four categories:
a familial syndrome (perforin deficiency)
associated with infection (Epstein-Barr virus, cytomegalovirus, parvovirus B19, bacteria, fungi, mycobacteria, and parasites)
associated with juvenile idiopathic arthritis (where it is usually called macrophage activation syndrome)
associated with immunodeficiency
DiGeorge syndrome should be excluded by FISH
Lysinuric protein intolerance – hyperammonemia is characteristic
the accelerated phases of Chediak-Higashi and Griscelli syndromes (both characterized by albinism, mutations in LYST or RAB27A genes respectively)
So do ferritin (spectacularly high,eg >1000)! And repeat if initially normal! Other bloods as above. ESR surprisingly low, due to low fibrinogen cf underlying JIA. All inflammatory markers can be low if very ill due to consumption.
Specialist markers include CD25, CD163, IL-18, CXCL9.
Diagnostic criteria perform well in specific settings but none perfect – get an expert! And go looking for underlying causes if not already known to have. Genetic testing in particular can dramatically impact on diagnosis and management.
MRI Brain and lumbar puncture for infants, known genetic disorder, or clinical indications – do cytopathology.
Treatment
For probable cases with worsening organ dysfunction, consider immunomodulatory treatment while diagnostic resting still ongoing. Empirical treatment can be high dose steroids, Anakinra or IVIG, plus treatment of underlying infection/malignancy.
[EULAR/ACR 2022 diagnostic criteria]
Oral Ondansetron use for gastroenteritis has become v popular in many emergency departments. In 1 study of 18 EDs, where it was a standard in nearly half all cases, there was no overall improvement in rates of either intravenous rehydration (remained around 18%) or hospital admission. There was a small decrease in re-attendance rates.
There was also a wide variation between institutions: perhaps the problem is not using Ondansetron it correctly eg not giving it soon enough, or rushing into IV fluids before allowing the drug time to work
Same group looked at Ondansetron in diabetic children with vomiting, again, usage increased from 0 to 67%. Admission rates dropped from 62% to 49% between these eras, as did use of IV fluids, but Ondansetron had no independent benefit.
From Archimedes Blog. (Freedman S et al. JAMA Pediatr 2014;168:321–29, see also Editorial)( (Leung J et al. J Pediatr 2014. doi.org/10.1016/j.jpeds.2014.10.020). )
Essential tremor develops insidiously and progresses slowly. May start in a single limb, but it becomes bilateral over time. Flexion-extension movement of the wrist, frequency of 4 to 12 Hz. May involve head (yes-yes or no-no). Worsens with stress, fatigue, and may increase with some voluntary activities eg holding a fork or cup. Rest, beta blockers, and alcohol help. Often a family history.
Compare Cerebellar tremor – low-frequency (less than 5 Hz), intention tremor. May include postural element (ie at rest). Other signs include abnormalities of gait and speech, nystagmus, dysdiadochonesis (inability to perform rapid repeated hand movements). Titubation is the word given to rhythmic movements of head/neck seen in cerebellar disease.
So ask patient to extend arms. Do Finger-to-nose, finger-to-finger, and heel-to-shin testing (Cerebellar). Observe drinking from glass, writing name, drawing spiral (or draw within lines of pre-printed spiral). Check for tone (rigidity), esp when busy using other limb, eg draw a circle in the air) – basal ganglia, eg Parkinsons. Check gait (shuffling? Ataxic?), eye movements.
Look for signs of space occupying lesion, thyroid or liver disease. Any chance of intermittent hypoglycaemia? Panic disorder? Withdrawal?
Children with congenital heart disease – Consider stopping domperidone therapy or discuss with parents/carers and ensure that cardiac monitoring is regularly performed. Consider offering an alternative treatment where appropriate.
Other children with established reflux or nausea and vomiting – Take no immediate action in patients already established on domperidone. Consider reducing the dose (where appropriate) to 250microgram/kg three times a day at the next convenient review. Consider routine cardiac monitoring where there are concerns (e.g. cardiovascular instability,
concomitant CYP3A4 inhibitors prescribed).
In new patients, always give a proper trial of feed thickeners before considering pharmacological intervention – at least two weeks. In more serious cases, and after the introduction of thickeners then consider the benefits and risks of medical anti-reflux/anti-acid secretion treatment.
If domperidone is to be used, give an initial maximum of
250micrograms/kg three times a day. Where reflux or nausea is refractory to
this then give increased doses to a maximum of 400micrograms/kg (max
20mg) three times a day and recommend regular cardiac monitoring.
Patient Information Leaflet entitled “Domperidone for gastrooesophageal
reflux” available from www.medicinesforchildren.org.uk
Long list of known risk factors, even though mechanism not clearly understood!
Age is probably the main risk factor – mostly 5-10 weeks of age. Very few in later infancy (although sudden death is described in all ages cf SUDEP).
From Scottish study –
So preterm, low birth weight boys with socially deprived unmarried mothers who smoke are at highest risk. But many of these factors compound and confound – 78% have at least 2 risk factors, only 0.8% have no risk factors. If you exclude “non-modifiable risk factors” (social deprivation, etc), only 5.3% have no risk factors.
Prone sleeping is no longer a major factor since it has been discouraged for years. Might be protective for preterms, where found to promote cortical arousal (CA) responses (protective in term infants). Horne 2013
36% of excess infant mortality in US South due to SUDI (90% of excess mortality in Kentucky! 59% due to non-hispanic black population).
Main risk factor now is co-sleeping, esp on sofa, although this is commonly associated with alcohol/drug use. Blair & Sidebotham BMJ 2009
Note used mattress is risk factor in Scotland – never replicated elsewhere.
Dummies are protective, even though they fall out – part of some national safe sleep recommendations but not in UK (perhaps because mechanism unclear?).
Parental mental health associated – if both have a mental health disorder, OR for SIDS =6, more if substance abuse disorder – but smoking/social deprivation explains 50% of this risk.
4% of unselected cases had long QT mutations [NZ] – increased to 16% when cases guided by cardiac genetics. But poor uptake of screening!
A previous maltreatment report emerged as a significant predictor of SIDS and other SUID. After adjusting for baseline risk factors, the rate of SIDS was more than 3 times as great among infants reported for possible maltreatment (hazard ratio: 3.22; 95% CI: 2.66, 3.89). [US, PMID 24139442]
has had 2 or more units of alcohol [not zero tolerance! Interesting…]
smokes
has taken medicine that causes drowsiness
has used recreational drugs.
And that’s it!!!
Note that the word “risk” is not used, just association! Boys as being at higher risk not mentioned!
PreBotzinger complex (preBotC) is a multi-functional neuronal network that is critically involved in the response to hypoxic and hypercapnic challenges.
Note increased brain oxygen requirement during “active sleep” cf quiet sleep. Only apparent between 2 weeks and 5 months. [Horne 2014].
Dutch recommendations include: (a) pre-term neonates born after 32 weeks should be placed in a supine position; (b) twins should not sleep in the same bed (‘co-bedding’); (c) use of a pacifier is recommended once breastfeeding is well underway; and (d) use of stabilization pillows is not recommended [PMID 23425715]
