Category Archives: Immunology

Allergy and mental health

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).

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).

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.

[Dunngalvin, Allergy 2020]

Systemic onset JIA

Features

  • Prolonged pyrexia (see below)
  • Intermittent characteristic rash (see below)
  • 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.

Juvenile Idiopathic Arthritis

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.
  • Reactive arthritis – can last up to 3/12.
  • Rubella, chronic meningococcus
  • HSP before rash develops
  • Rheumatic fever
  • Behçets – mouth/genital ulcers, uveitis.
  • 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.

Uveitis

The Uvea is the term for the whole eye (uvea=peeled grape). Whereas conjunctivitis looks like a red eye, it’s only really the surface that is inflamed. With uveitis, all the different tissues of the eye are inflamed. Acutely, might not look that different to conjunctivitis but painful, whereas latter usually just itchy. Anterior chamber starts to fill up with inflammatory cells so vision starts to deteriorate. An irregular pupil due to synechiae can eventually be seen, with hypopyon. Cataracts and scarring can follow.

Chronic on the other hand can be subclinical but potential for visual loss so screening important in associated conditions.

Usually idiopathic, otherwise:

  • Juvenile idiopathic arthritis – about 10% of patients with non-oligoarthritis, and 30% of ANA positive oligo so pretty common
  • HLA-B27 – with or without other B27 conditions such as Ankylosing spondylitis
  • Behcet’s disease (so do HLA B51)
  • Crohns disease and other IBD
  • Granulomatosis with polyangitis (ex-Wegeners)
  • Sarcoidosis (so do chitotriosidase)
  • Tubulointerstitial nephritis and uveitis (TINU) syndrome

Some infections can cause it:

Wheat allergy

Talking here about type 1 IgE mediated wheat allergy. Not coeliac disease, which is an autoimmune process triggered by gluten.

Only 10% persists to adulthood, equivalent to milk/egg.  Max IgE over 20 has median resolution age of 7, rises to 16 if max over 50. Unusually, IgE often remains positive even when tolerance has developed! But trend still useful for individual patient.

Wheat allergens – most commonly LMW glutenin, alpha and gamma gliadins, NOT omega. Technically gluten is found only in wheat, and is a complex of gliadin and other proteins, similar prolamins in other cereals have different names eg zein (rye), avenin (oat), hordein (barley)! 

Level of omega 5 antibodies correlates with clinical severity of exercise induced anaphylaxis! Not specific though – Omega 5 antibodies are present in 80% with anaphylaxis to wheat (non-exercise induced) and 20-30% of wheat allergic with eczema. Useful for predicting anaphylaxis??

Note that those with grass pollen allergy often have non clinically significant IgE to wheat.

[Nutrients 2017 – doi: 10.3390/nu9010035]

Lots of different names for wheat versions/products – Bulgar wheat, couscous, durum wheat, freekeh, einkorn, emmer, farola, kamut, malted wheat, semolina, spelt, triticale, wheat bran, wheat germ.

Presence of wheat starch in gluten free products (can be useful for producer) means the low level permitted for coeliac disease may still cause reactions if sufficient amount eaten, so avoid wheat based gluten free products if type 1 allergy.

But glutens present in non-wheat grains are not usually a problem for type 1 wheat allergy, so excessively restrictive to follow gluten free labels on things not made with wheat, eg oats!

Testing often suggests cross reactivity between different cereals but when you actually challenge, majority only react to one, and non wheat allergies pretty rare. Oat, rye, barley allergy uncommon. Maize allergy seen more with Southern European fruit allergy syndromes.

And strange how aeroallergy so rarely translates to food allergy and vice versa [(J ALLERGY CLIN IMMUNOL 1995;96:341-51]

So I would say no need to avoid or test unless symptomatic.

Cross contamination (as in coeliac) a big issue – crumbly! Toasters, butter, surfaces etc.

Hydrolysed vegetable protein sometimes comes from wheat, has to be declared as allergen but little evidence that it is still allergenic.

Reports of allergy to deamidated wheat (“wheat protein isolate”), where tolerant to normal wheat. Found in cosmetics too.

Hay fever

=allergic rhinoconjunctivitis due to seasonal triggers, typically grass and/or tree pollen. First described by John Bostock in 1819! More likely if born in early months of year!

So itchy, swollen, watery eyes, runny and/or blocked nose, sneezing. Often itchy throat and ears too. Cobble stone appearance can be seen at the back of throat.

Not dangerous, but can seriously affect quality of life: poor sleep, poor concentration (exams usually at worst time of year), embarrassment about snot. One study showed children in England were less likely to get their predicted exam grades if they had hay fever, especially if prescribed sedating antihistamines.

Associated with other atopic conditions, such as food allergy and asthma. Under recognized as trigger for asthma exacerbations – pollen is too large to trigger the lower airways directly, rather pollen exposure in the upper airways trigger inflammation that travels down over a period of weeks to the lower airways. An exception is when pollen grains are fragmented, as seen in thunder storm asthma [Australia, Clin Exp Allergy. 2018;48:1421‐1428]

There are many different species of grass, but if allergic to one you tend to be allergic to all of them. Trees on the other hand vary, you tend to be allergic to specific groups of trees. In Europe the most important are birch (northern Europe) and olive (Southern Europe). Birch is related to alder, hazel, beech and oak.  Olive is related to ash.  Weeds belong to various unrelated families.

Hazel trees can start producing pollen in February, weeds can continue produce pollen through September! Moulds seem more associated with asthma than hay fever. Cypress blooms in winter! 

It’s not just pollen count – the amount of allergen carried by the pollen varies too. Correlate pretty closely but varies by time and place. Pollen potency varies (4-5 fold difference) geographically, especially grass. France has the highest yearly average grass pollen potency, 7-fold higher than Portugal. Olive pollen from two locations 400km apart varied 4-fold in their allergen potency – in Portugal there are times when pollen from Spain probably more of a problem for triggering hay fever than pollen from “local” trees! [Health Impacts of Airborne Allergen Information Network (HIALINE project)]

Management

Watch the pollen count, and choose activities accordingly. Pollen levels fall in evening in countryside, but in cities not until 1am! There are apps that can help with this.

Closing windows, or at least not sitting near windows, washing hair, not drying clothes outside, pollen barrier balms.

Choose where you are going on holiday carefully!

Antihistamines – oral or nasal. Various, some people find one works better than another Sedating antihistamines eg Chlorphenamine should be avoided except at night. Nasal steroids useful if used correctly. Combination steroid/antihistamine available. Leukotriene receptor antagonist licensed for hay fever in children with asthma.

Short courses of oral steroids might be justified for special occasions.

Immunotherapy available – deaths reported in asthmatics with poor control.

Sublingual – age not important cf ability to hold in mouth for 2 minutes. Not approved by SMC in Scotland yet. Combined grass and house dust mite coming.

[Sian Ludman, St Mary’s]

For symptoms all year round (perennial), triggers such as house dust mite and pets are more likely.

Tree nut allergy

Group of nuts that includes hazelnut, almond, brazil nut, cashew, pecan, pistachio, walnut and macadamia. Definition of nut is actually a bit complicated, to do with whether the shell comes off spontaneously or not, but I stick to those defined by food labelling law.

Does not include peanut (a legume), coconut, pine nut, chestnut or tiger nut.

You can be allergic to just one, a couple or the whole lot. Risk of allergy to peanut is higher than if you weren’t allergic to anything.

Hazelnut and cashew allergies are common. Almond rare.

Hazelnut allergy goes along with fruit allergy and oral allergy syndrome.

Cashew allergy goes with pistachio allergy. Cashew allergy is particularly associated with anaphylaxis, even more so than peanut (but less common as allergy and allergen so less well known).

Pecan allergy goes with walnut allergy.

Hazelnut allergy

One of the tree nuts. One of the most common food allergens in the UK. Adults seem to get less severe reactions than children. Anaphylaxis rare compared with peanut and other tree nuts.

Hazel tree is related to birch, and indeed hazelnut allergy can be associated with tree pollen allergy (hay fever), as well as fruit allergies.

Cor a 1 is the least likely to cause systemic reactions, and then only with raw cf roast.  Cor a 8/9/14 associated with systemic, although 8 is LTP so may only be local (and likely fruit allergy too) – probably seen more often in Mediterranean populations. The others are storage proteins so more likely to cause severe reactions.

Cor a 9 and 14 seem most useful  – >1kU/l and/or >5 respectively give specificity of >90% and sensitivity of 83% in kids for “allergy with objective symptoms” viz more than just a tingle/itch. That translates to a negative predictive value of about 93% (PPV not given). [Dutch study, JACI 2013;132(2):393]

German study found  Cor a 14 had best AUC (0.89, cf 0.71 for whole hz).  Level of 0.35 gave 85% sensitivity with 81% specificity.  PPV doesn’t hit 90% until 47.8 though…

SARS-CoV-2 vaccine

Multiple vaccines in the pipeline, mostly against spike (S) protein in SARS-CoV-2 that facilitates host cell entry.

Pfizer vaccine is mRNA vaccine, completely in vitro derived, uses nanoparticles to aide absorption into host cells which then produce the S protein themselves from the mRNA. AstraZeneca vaccine is chimp adenovirus vector for genetic sequence – mRNA produced once virus taken up by host cell.

Single dose IM injection.