Substantial evidence that alterations in the gut microbiome early in life “imprint” gut mucosal immunity, which is probably important for development of food allergy.
Maternal factors, timing and how solids introduced all likely to be important.
Similarly, the “exposome” is the term for external factors influencing epithelial barrier immune balance – damage, inflammation, colonization, dysbiosis, translocation etc.
Great data from studies of Hutterite vs Amish populations in the US (same origin in Austria) – Amish are more traditional farmers, low technology use, v low atopy rates. See more on the farm effect on allergy here.
Transplacental factors discussed by Patrick Holt (Perth, WA) in 2009 (“soothing signals”).
MV130 is heat inactivated cocktail of bacteria – in RCT (n=120, under 3yrs) 6 months SLIT reduces episodes of recurrent wheeze by 40% in children, also lower duration and symptom scores. [Antonio Nieto, Madrid]
COVID 19 has shown how innate immunity isn’t actually fixed, and can be trained (“trained immunity”) esp BCG, LPS.
Experimental studies have shown that faecal transplants or other attempts to modify bacterial commensals can prevent or treat food allergy as well as asthma.
Mechanisms include restoration of gut immune regulatory checkpoints (eg retinoic orphan receptor gamma T+ regulatory T cells), the epithelial barrier, and healthy immunoglobulin A responses to gut commensals.
Usually just a marker of atopy, so common with asthma, hay fever, eczema. Mild generally accepted as 0.5–1.5×109/L, moderate 1.5–5, and severe >5. Persistent would be over 2 weeks.
But beware rare things eg HyperIgE syndrome. Any evidence of organ impairment? Also seen with malignancy, PFAPA, Familial Mediterranean Fever. With the rheumatological conditions, eosinophilia is often severe (>5) but with malignancy, usually mild…
Described in 2015, revolutionary in that allergy is to an oligosaccharide (ie a sugar, not a protein), specifically galactose-alpha-1,3-galactose.
Accounts for anaphylaxis to cetuximab, a cancer drug, but even more bizarrely, allergy to red meat (beef and pork). The latter appears to follow sensitization through a tick bite, so is really only an issue in endemic areas eg parts of United States and Europe, Australia.
Anaphylaxis to red meat can be immediate or delayed, with or without exercise induction!
In a small series of beef allergic patients reported in 2003 (strong family history), skin prick and labial contact tests only positive in minority. All positive on IgE. In another series, most beef allergic were also gelatine allergic. Risk from gelatine is mostly from intravenous products, but big dose of jelly sweets as risk??? Interestingly, a proportion of “idiopathic” anaphylaxis turned out SPT positive for gelatine.
Bovine specific albumin (Bos d6) is another possible allergen for beef allergy – a minor cow’s milk allergen, so you would probably react to both – heat labile.
In Asia allergy described to galacto-oligosaccharides in
milk formula, also a carbohydrate!
Thought to be T cell independent!
IgE test available. Levels appear to fall over time unless continued tick exposure.
Emerging? Changes in land use (less sheep, more deer)? About 50 cases in Scotland (2025) – certainly not all rural so prob recreational exposure. Youngest 4yrs (Argyll). Mostly strongly co-factor modified; cf America (big steaks?)
Maize is also known as corn in English, but in America “corn” refers to wheat, so potential for confusion! Commonly used in Mexican cooking.
Allergy to maize is extremely rare. It is not one of the 14 allergens that has to be highlighted under UK/European law on ingredient labels. Cross reactivity with wheat, rice and other cereals seen on lab tests but rarely clinically relevant. It does seem to fit more with Southern European fruit allergy syndromes, including sunflower seeds.
Foods:
Sweetcorn, corn on the cob
Popcorn
Cornflakes and other breakfast cereals
Corn flour (used as a thickener so can be low level in lots of different things)
Baking powder often contains corn flour
Custard
Tortilla chips, tacos, nachos
Most wraps are made of wheat but some are made with maize or a mixture of the 2
Some of the toddler snacks by Organix/Ellas Kitchen etc
Cornmeal, used to make polenta and grits
Potentially corn flour could appear in tablets/medicines.
There are some reports of severe allergic reactions to fructose syrup derived from maize/corn, which is used in lots of things (including beer and other drinks). This probably isn’t a problem for most people with maize/corn allergy though, so you should only avoid this if anaphylaxis or likely previous reactions to it.
Corn oil certainly poses no allergy risk, as processing removes any allergenic proteins.
The name for pure natural rubber. Found all over the place – foam (mattresses), condoms, balloons, seals, adhesives. In hospitals, BP cuffs, elastic bandages, catheters and ET tubes, pulse oximeters… Not so often in surgical gloves now. Can cause mild and severe (anaphylaxis) reactions, plus delayed (non type 1) allergy. Allergy first described in 1979, became epidemic in 1980s.
The rubber tree Hevea brasiliensis is not the same as “rubber plants” (Ficus) you get as pot plants, although you can be allergic to those too, of course.
About half of latex allergic patients also have fruit allergies, especially avocado, banana, kiwi, melon but also chestnut and tree nuts.
Certain high risk groups:
Spina bifida
Health care workers
Atopic or irritant dermatitis may also be caused by rubber chemicals rather then latex itself.
Diagnosis
Blood IgE test – as with other IgE tests, potential for false positives esp with grass/fruit allergy.
Skin prick test with standardised latex
Prick through suspected glove! Needs latex free environment, of course. Potential for reaction to powder, rather than latex…
Glove test – wet hand! Risk of anaphylaxis.
Risk of Anaphylaxis
As with other allergies, seems to vary between individuals. And previous reactions do not reliably predict future reactions.
With health care, difficult. First on surgical list. Label patient. Latex free environment, as far as possible. Reports of probable reactions from IV fluids and needle puncture of bungs in IV sets.
Evidence that having a peanut allergy has worse quality of life for a family than having diabetes… Mostly due to fear of unexpected severe reaction, and restrictions on social activities particularly eating out, parties and holidays.
Allergic patients can feel embarrassed or even ridiculed for declaring their allergy. Allergy is often mocked in the media (Cobra Kai, the Box Trolls, Peter Rabbit), asthma in particular.
School and nursery are a particular area of concern, whether the right foods will be served, whether teachers or other children might bring allergens into school (food is sometimes used in classes, for example making bird seed balls), whether reactions will be managed appropriately, school trips. Children have died in school (Nasar Ahmed, Mohammed Ismaeel Ashraf).
APPEAL study 2022 – UK & Ireland, peanut allergy – 87% of parents/care-givers (not clear if mums or dads) felt moderately or severely restricted eating out, choosing where to eat (82%), special occasions (76%) and when buying food from a shop (71%). 52% of survey participants reported being bullied because of their allergy. But variable – some feel allergy has minimal impact on their health-related quality of life.
Mums tend to be more concerned by limitations in the child’s own social life, dads seem to care more about limitations in the whole family’s social life. [Stensgaard, Clin Exp Allergy 2017]. Mums are the ones most studied. There probably are significant differences between mums and dads. In some studies, parents overrate their child’s quality of life, but in others (particularly with teenagers) parents can be seen as over anxious. Teenagers tend to take on the perspective of the parent of the same sex.
How bad previous reactions have been, interestingly, does not in itself contribute significantly to quality of life – in some cases, not having ever had a reaction can make families more anxious, because they don’t know what to expect! In one study, having multiple allergies and having an adrenaline pen was associated with worse quality of life. [Protudger, Clin Transl Allergy 2016]
Parents can feel guilty if their child has a reaction, a failure of their duty to protect. Mums can feel guilty about having “caused” their child’s allergy, either through their own medical history or what they ate or didn’t eat in pregnancy (even there is no good evidence for this being a factor).
Better quality of life is seen in allergic families with greater self efficacy for food allergy management, and lower perceived likelihood of a severe reaction [Knibb, Pediatric Allergy & Immunology. 27(5):459-464, August 2016].
APPEAL-1 study
8 European countries, questionnaire study of adults and children with peanut allergy.
Only a minority remembered getting any training in future
emergencies or use of medication, after their initial reaction. There was a low
rate of satisfaction with AAI training!
43% reported bullying, and a third of these described it as
severe.
65% confident in ability to recognize a reaction, but only
45% confident about knowing when to use an AAI and 59% how. 62% say the carry AAI all the time.
25-30% said it was not easy (or rarely easy) to talk to
friends or family about their allergy, although most felt confident talking to
new people about their allergy. Friends and family were generally seen as “believing
there is too much concern over allergy” even though overall they were seen as
having a good awareness and understanding of allergy (cf other people, where
this was seen as the opposite).
Dutch respondents had lowest rates of uncertainty and stress
around activities, and for feeling anxious.
At same time, they had the highest rates of confidence around knowing
when and how to use AAI. France had
highest rate of being made to feel different in a negative way, and feelings of
isolation.
NB – likely to be the most affected families who
participated.
Raised CRP, ESR, ferritin (esp over 1000 – also haemophagocytic syndromes, haemochromatosis, liver disorders, malignancy)
Poor response to IVIG (cf Kawasakis)
Leucocytosis (neutrophilia, can be leukaemoid)
Thrombocytosis
Arthritis
Hepatosplenomegaly
Generalised lymphadenopathy
Pericarditis
Can be systemically very unwell and potentially life threatening complications may occur early in the disease course (eg pericarditis, macrophage activation syndrome or HLH, sepsis). See the Big Sick film from Netflix. Start high dose corticosteroids after careful exclusion of other diagnoses, especially infection, Kawasaki disease, and malignancy – difficult when arthritis is absent! But maybe you have to look harder…
Systemic features may predate the arthritis by several weeks and occasionally longer. Typically involves small joints of the hands and wrists, ankles, hips, knees, and cervical spine – about 30% ultimately develop severe polyarthritis.
There are no pathognomic tests or agreed diagnostic criteria for SOJIA! Classic features:
quotidian (=daily) evening spiking temperature, that returns to or falls below baseline by the morning.
Rash is faint, salmon pink maculopapular, most obvious during pyrexia. Usually not on the face so easily missed – typically on the trunk, inner thigh and axillae, especially on areas of trauma or pressure (Koebner phenomenon).
Treat with IV methylprednisolone pulses (30mg/kg over 4 hours, max 1g, once daily for 3 days) and ibuprofen (seems better than piroxicam for SOJIA!). Oral prednisolone may then be used while methotrexate is introduced.
Seven subtypes – only diagnose when symptoms for at least 3 months:
Oligo (persistent or extended) – Arthritis affecting up to four joints during the first six months of disease. If subsequently more than four joints are affected the term extended oligoarthritis is used, otherwise the term persistent oligoarthritis is used. This is the most common pattern (50% of all JIA) and usually involves large joints of the lower limbs, especially knees. These children have the best prognosis but are at high risk of asymptomatic uveitis (30%, and risk highest in monoarthritis!) and therefore must be screened regularly. In aggressive disease, can develop within 3 months of presentation. Girls mostly ankles, knees or wrists, 50% will be ANA positive and particularly associated with chronic (even subclinical) uveitis. Boys tend to get sacroiliitis and are HLA B27 positive, which is associated with acute uveitis…
Polyarthritis (rheumatoid factor -ve) – 5+ joints affected during first 6 months. Tends not to be hips! 17% of all JIA. Severity is very variable.
Polyarthritis (RF +ve) – 7% of all JIA. Symmetrical polyarthritis, nodules, and Rheumatoid factor IgM +ve at least twice, 3 months apart. Typically adolescent girls of 10yrs+. Prognosis is guarded as early joint damage often occurs.
Systemic onset – SOJIA, 11% of all JIA. Can occur at any age, often pre-school but rarely in infancy. Males and females affected equally.
Enthesitis related arthritis – inflammation of tendon insertions eg sternum, around knee (at 2,6 and 10 o’clock positions), tibial tubercle, achilles/plantar, tibialis anterior, flexor digitorum insertion in foot. Often dactylitis. Asymmetric, distal lower limbs large joints commonly affected, high risk of developing ankylosing spondylitis in early adulthood – spine rarely affected early on. BASMI score consists of 5 measurements of spinal mobility. The group also includes arthritis or enthesitis with at least two of:
tenderness of the sacroiliac joint and/ or inflammatory spinal pain
HLA B27 positive (10% of normal population)
family history in a first or second degree relative of HLA B27 related disease (ie arthritis, IBD, Reiter’s, uveitis)
anterior uveitis (usually symptomatic with redness, pain and blurred vision)
arthritis after 8 years of age in a boy (esp large lower limb joints).
Psoriatic arthritis – esp umbilicus, behind ear, scalp. The arthritis is usually asymmetrical, mixed large/small joints. Often NOT psoriasis, at least initially, but includes children with arthritis and at least two of:
dactylitis (fat, sore fingers!)
pitting or onycholysis of nails
psoriasis in a first degree relative
Other arthritis – This group is for children with idiopathic arthritis that does not fit the other groups (or into more than one! eg Crohns & UC associated arthritis, features overlap). Downs syndrome children can get a resistant polyarthritis.
Presentation
Clinically, history of pain, swelling, stiffness. Pain is usually not severe, and often avoided completely by adapting movement; can occur at night, and occurs in the joint line. Degree of pain does NOT predict severity of synovitis. Swelling may be due to effusion or bony overgrowth. Stiffness not so severe as to cause gelling ie sitting still leads to freezing (cf myasthenia gravis, hypermobility). Bony overgrowth, discrepant leg length (longer with inflammation! Leads to postural scoliosis), wasting show chronicity.
Differentials:
Benign hypermobility – typically get pain related to exertion, short lasting although may occur at night.
SLE (high ESR with normal CRP, low WCC/platelets, autoantibodies) or dermatomyositis (stiffness, rather than true arthritis – proximal muscle weakness, high CK)
Investigations:
Mono JIA usually CRP <7 – else beware infection
Micro of joint fluid nonspecific
XR – to exclude tumour etc. Lucency in metaphysis may be marrow infiltration in leukaemia, Brodie’s abscess or Langerhans’ histiocytosis. Moth eaten appearance and onion skin periosteal reaction suggests tumour or infection.
RF v non specific, like autoantibodies, only significant in discriminating teenage girls with adult type Rheumatoid Arthritis.
US is good but operator dependent. MRI probably better, predicts extension in mono, 4-11/12 before clinical signs.
Treatment
NSAIDs and intra-articular steroids work quickly. Ibuprofen can be given at high dose (10mg/kg qds), else Diclofenac 3-5mg/kg in 3-4 divided doses, max 150mg. Piroxicam is once daily, which is convenient but it probably has more GI/cutaneous side effects. No longer considered appropriate for acute pain.
Routine NSAIDs are probably pointless; if you need regular anti-inflammatories, you should probably be on a disease modifying agent eg methotrexate.
Joint injections are given under general anaesthetic in young children or with entonox in older children. Lederspan (triamcinolone) 1mg/kg max 40mg used for big joint, 0.5mg/kg for wrist, TMJ. Knuckles will only take 0.1-0.2ml before they start to leak (which leads to subcut atrophy). Injecting multiple (eg >6) sites can result in Cushings for 3-6/12. Better to pulse methylpred? (Kennilog is another formulation, but seems to give more Cushings). Most patients tolerate injections well and have no loss of function immediately after; physio is usually started after 24hr. How often? Balance of steroid effects and uncontrolled joint disease…
Methotrexate Side effects: GI (nause, ulceration, diarrhoea), hepatotoxicity (reversible elevations of serum liver enzymes eg 3x upper limit normal common), Pulmonary (oedema, pleuritic pain, pulmonary fibrosis, interstitial pneumonitis), mood changes, Renal (haematuria, dysuria, renal failure) – plus usual chemo stuff ie bone marrow suppression.
BNFc
Methotrexate is the disease modifying drug of choice – early use helps to reduce joint damage and minimise the exposure to, and side effects of, corticosteroids. Well tolerated in most children but often causes nausea the day after administration (so usually given on Friday to avoid affecting school). Avoid alcohol, as potentiates risk of cirrhosis. Takes 6-8 weeks to become effective so cover interval with intravenous methylprednisolone. The theoretical risk of malignancy and infertility has not so far been borne out in long term outcome studies. Folic acid improves tolerability but not clear what regimen to use – BNF suggests 5mg once weekly or 1mg daily, theoretically it should not be given within 24 hours of the MTX [so once weekly sounds easier]. Methotrexate is given once a week at 10-25mg/m2 – can be oral but subcut route improves bioavailability at doses beyond 10mg/m2. Metojet has better shelf life (10 months). Regular blood tests to monitor inflammatory markers and side effects eg monthly for 6 months then 3 monthly thereafter. Not great for axial disease ie HLA B27.
Steroids are useful for treating acute flares. Methylprednisolone can be given once daily for 3/7 to control severe exacerbations, then once weekly thereafter (30mg/kg, max 1g). Don’t work well for axial disease though ie HLA B27 (although may be good for peripheral joints) – TNF blockade (ie etanercept or infliximab) effective.
Patients who are refractory to high dose parenteral methotrexate are considered for monoclonal antibodies such as Etanercept/infliximab (TNF antibody), autologous stem cell transplantation, or very high dose immunosuppression.
Etanercept (Embrel) used to be twice weekly subcut injection but most now do once weekly 0.8mg/kg. £10 000pa.
Infliximab is an infusion, given at 0, 2, 6 weeks then 8 weekly thereafter. Children usually start at 5mg/kg. If control not achieved, a higher dose could be used else the interval reduced. Patients should get a CXR and Mantoux before starting in view of the particular risk of mycobacterial disease.
IV immunoglobulin has been used eg 2 doses on consecutive days monthly. Very expensive.
Mycophenolate – related to azathioprine. Used for connective tissue disease. SE gastrointestinal, liver, bone marrow. 600mg/m2 BD
Calcium and vitamin D supplements are often given for bone health.
Patients on immunosuppressants should avoid live vaccines and beware of infection. If unwell enough to need antibiotics they should probably stop treatment temporarily. Varicella is a particular concern – if contact with chickenpox and non-immune, consider VZIG or oral aciclovir for prophylaxis, and early IV aciclovir treatment. See Greenbook.
Not clear when to wean… Many patients do well for a year or so before their condition begins to worsen, swapping to another agent often works, and swapping back is also a useful option.
Outcome
JIA is a not a benign disease and outcome is variable. At least a third of patients have ongoing active disease into adulthood and many have sequelae eg:
joint damage requiring joint replacement
short stature from chronic disease compounded by steroid toxicity
localised growth problems (micrognathia or leg length inequality)
visual loss from uveitis
osteoporosis: one off DEXA scan not predictive of # (maybe better if serial scans?) so clinical. Minimize steroids; optimize exercise, nutrition, growth/puberty, calc/vitD/bisphosph
Bisphosphonates seem to be effective for increasing bone mass in JIA. Flu-like symptoms with first IV dose can be treated with paracetamol and tend not to recur.
