Category Archives: Immunology

Immunotherapy

Allergy, General paediatrics, Immunology, , ,

First described in the literature in 1908! For egg. Noon and Freeman described grass immunotherapy in 1911. First double-blind trial was by William Frankland in 1954 for subcutaneous grass immunotherapy for seasonal asthma.

Should always be done with extreme caution, if at all, if asthma.  Available for wasp/bee stings, grass and tree pollen.  Lots of evidence for food allergies, especially in younger children eg peanut immunotherapy.  House dust mite sublingual now approved by NICE for resistant allergic rhinitis.

Some evidence that immunotherapy for rhinitis also prevents asthma, which fits with “one airway” hypothesis.

Immunotherapy should be initiated and monitored in a specialist centre experienced in immunotherapy.

Text message reminders doubles adherence – even non-personalised.

Immunomodulation with omalizumab appears to improve success rates of immunotherapy. Treatment with dupilumab (anti-IL4/13) reduces specific IgE levels in people with atopic dermatitis (clinical effect unknown just now).

Grass/pollen allergy

EAACI indications for rhinoconjunctivitis immunotherapy includes:

  • mild rhinitis for reasons of asthma control.
  • Moderate-severe symptoms.

Bad asthma and poor compliance are contraindications. Bad asthma was an exclusion criterium for most of the studies, so no evidence of safety.  Poor evidence for under 5yrs (for HDM).

Polysensitization common, US tend to to treat all, Europe tends to pick 1 or 2 most useful, at intervals. 17 fatalities to date with immunotherapy. 1 per million injections (risk with sublingual much less, even though used for higher risk patients). Large local reactions common but don’t predict further reactions. Risk of systemic reaction only increased if recurrent. Consider predosing with antihistamine, else reduce dose.

Sublingual immunotherapy (SLIT) in children aged 4 to 12  years with grass pollen-allergic rhinitis/rhinoconjunctivitis significantly  reduced symptoms and medication use, well tolerated, and no serious treatment-related  events were reported. [Journal of Allergy & Clinical Immunology.  130(4):886-93.e5, 2012 Oct.]

In metanalysis by Dhami S et al, overall standardized mean difference (SMD) of -0.53 (95% CI -0.63, -0.42) in symptoms scores, roughly equal numbers of SCIT and SLIT studies, roughly equivalent scores.  When looking just at children, benefit seems less (SMD -0.25 (95% CI -0.46, -0.05)).  Continuous treatment probably slightly better than pre/co-season treatment.  Manufacturers suggest “disease modifying effect” of treatment beyond first year, which has theoretical rationale.  Four studies of long term outcome, demonstrates continuing benefit if treatment continued beyond first year [Allergy 2017]. 

Grazax (grass) can be safely administered by general practitioners (£80 per month, licensed from 5yrs up): tablet needs to be kept under tongue for at least 1 minute, first dose should be monitored by doctor for 20 minutes.  Don’t eat or drink for 5 minutes.

Give antihistamines for local effects. Oral blistering occurs!  Isolated cases of eosinophilic oesophagitis but impossible to link of course.

Contains fish gelatine but no reported problems in those with fish allergy.  Severe asthma contraindication (in children, defined as <80% predicted FEV1 on treatment).

Aim to start 4 months before season starts, although still some benefit if started 2-3 months before.  If no benefit in first season, no point continuing (according to Grazax own SPC).

Symptom relief begins only in the second season of therapy?  BNFc says continue only for 3 yrs.  Not approved by SMC for Scotland, because no great evidence for benefit after first year – would need individual patient treatment request.  Rosie says children wouldn’t tolerate daily doses for months and years.

Pollinex subcut, given into middle third of upperarm.  2 versions: Trees, and 13 grasses incl rye. 3 injections at 7-14 day intervals each year (£450 each), before season starts.  Maintenance kit of 4 vials also available, presumably if additional benefit thought possible.  Manufacturer recommends using for 3 successive years. Asthma and beta blocker treatment are relative contraindications.  Age 6+, not in SMC at all. [Metanalysis, Chest 2008; 133:589, Journal of Allergy & Clinical Immunology. 115(4):676-84, 2005 Apr.]

Some evidence for short course – in multicentre study of adults (not UK) with grass mix SPT positive rhinitis, 8 subcutaneous injections of placebo or Lolium perenne (LPP) were administered in 4 visits (2 jabs each visit, 30 mins apart, different arms) over 3 weeks between January and April. Combined symptom and medication score (CSMS) measured over the peak pollen season was reduced 15.5% (P = .041) during the peak period and −17.9% (P = .029) over the entire pollen season. Also lower rhinoconjunctivitis QOL global score (P = .005) compared with placebo group.

Asthma

Dhami metanalysis immunotherapy for asthma in kids – symptoms improved, less medication, esp HDM, grass, cat/dog. Not just severe asthma! But no prolonged benefit.

1 study of adults with poor control, HDM. Reduces time to first exacerbation.

Mite allergy prevention study n=111 HDM treatment effective. 2002 PAT study reduced asthma at 10yr follow up after grass/pollen treatment.

[Gillian Vance, Newcastle]

Eczema

House dust mite immunotherapy with SLIT (3 doses per week) shown to have some benefit in RCT from Brazil (66 children and adults) using SCORAD eczema severity questionnaire. Placebo group showed 35% improvement over 18 months, SLIT group showed 55%. No difference in Dermatology Life Quality index, pruritus score or any of the various other measures used!

Varicella Zoster Virus vaccine

General paediatrics, Immunology, Infectious disease,

Following varicella vaccine introduction in Australia, coverage of greater than 80% at 2 years of age was achieved, with varicella hospitalizations reduced by almost 70%. 40% of hospitalized children were immunocompromised.  Of hospitalized children age-eligible for varicella   vaccine, 80% were unimmunized, including all cases (3) requiring intensive care.  No deaths.

[Pediatric Infectious Disease Journal. , 17 December 2012]

Eczema

Dermatology, General paediatrics, Immunology,

NICE (CG57, 2007) diagnostic criteria:  itchy skin plus 3+ :

  • visible flexural dermatitis (or visible dermatitis on the cheeks and/or extensor areas in children <18/12) – can look like dirt where darkened esp neck
  • personal history of flexural dermatitis (or dermatitis on the cheeks and/or extensor areas in children  <18/12)
  • personal history of dry skin (xerosis) in the last 12 months
  • personal history of asthma or allergic rhinitis (or history of atopic disease in a first-degree relative of children aged <4yr)
  • onset of signs and symptoms under the age of 2 years (do not use this criterion in children under 4 years).

On examination, may also see lichenification (increased skin markings due to chronic rubbing), excoriations caused by scratching, and hyperlinear palms (look at thenar eminence).

Risk factors

Eczema (or atopic dermatitis, same thing) associated with parental allergies (OR 1.94), parent-reported infection after birth (OR 1.45), parent-reported jaundice (OR 1.27). Being a migrant (OR 0.63) and keeping a dog (OR 0.78) are protective. Prenatal probiotics did not reduce risk (Lactobacillus rhamnosus GG, LGG).  Respiratory viral infections in pregnancy associated with wheezing illness in infants (mothers with asthma) and eczema.  [Australia, Ped All Imm 2014:25:151].  Febrile and gynae infections in pregnancy associated with eczema in child (Italy, Ped All Imm 2014:25:159].  Children of Japanese mothers with higher anxiety scores during pregnancy were more likely to be affected by eczema!

Immunology

Many roads lead to Rome!  Can be seen as combination of impaired innate and distorted adaptive immunity, interacting in framework of cutaneous immune system with suboptimal barrier function.  Epidermal barrier can be genetically disturbed, but gene expression (eg of filaggrin) is also influenced by microenvironment eg Th2 cells.  Some genetic structural abnormalities can be seen to induce nonspecific inflammatory reaction (eg SPINK5 defects).  And almost certainly, epigenetic regulation will affect gene expression in both keratinocytes and immune cells.

Facilitated antigen presentation mediated by IgE bound to high affinity IgE receptor FcEpsilonRI, on dendritic cells, is an important part of it.  Vitamin D plays a key roll, stimulates Toll like receptors, increasing pro-inflammatory cytokines but studies equivocal whether low (or indeed high) levels increase risk.

Eczema can exist without IgE against aeroallergens and food allergens, so is primarily a non IgE mediated disease, although both IgE and non-IgE hypersensitivity can co-exist, particularly in babies.

Still not understood how eczema and Staph aureus interact.  Colonization appears to amplify local inflammatory reaction, but also increases IgE against a large spectrum of other things (possibly including self proteins).  It is as if there is something specifically different about how immune cells handle Staph.  Toll like receptors esp TLR-2 recognize Staph aureus cell wall. Overgrowth of staph during flares is associated (preceded?) by loss of diversity of skin microbiome.

Unmasking of the HSV entry receptor Nectin-1 in adherence junctions, among other things, contribute to eczema herpeticum.  See Flares, below.

Atopy patch test (using intact protein allergens) can prove type IV reactions. Correlates with oral food challenge. Hyper IgE syndromes are important differential for AD, STAT3 mutations, skin (and other) abscesses, recurrent pneumonia (and pneumatocoele), connective tissue and skeletal abnormalities, mucocutaneous candidiasis. DOCK8 type Hyper IgE syndrome show sensitization predominantly against food allergens, which is a clue (STAT3 and AD show predominantly sensitization to aeroallergens).

Normal looking  skin is not immunobiologically normal!  Invisible inflammation, hence still needs treatment. Pimecrolimus and betamethasone both normalize expression of filaggrin, the later is perhaps a better anti-inflammatory but steroids reduce expression of enzymes for lipid and protein synthesis, so may impair skin barrier restoration.

Triggers

Stress, humidity, extremes of temperature can cause flares of atopic eczema. But what causes a flare in some can apparently help in others! Any factors causing flares should be avoided where possible.

UVB causes sunburn.  UVA (longer wavelength) more relevant to photosensitivity reactions.  Both cause long term skin damage.  EU commission recommends UVA protection making up at least 1/3 of total suncream SPF.  A few available on prescription for photodermatosis (incl vitiligo) but not for eczema per se.  Lipscreen (Uvistat) available for chronic/rec HSV labialis.  Sunsense is lotion.

Avoid wool in contact with skin.  No evidence that bio detergent or fabric softener a major problem.  Avoiding excessive product and not overloading machine (so disperses fully) prob more important.

Management

See eczema management.

Parental support

National eczema society, British Association of Dermatologists, Eczema Outreach Scotland.

Scombroid Poisoning

Allergy, Immunology,

Differential diagnosis to allergy. Basically Histamine poisoning, rather than release of endogenous stores! Mild examples are not uncommon but severe cases rare. Clue is that several people who eat the same seafood meal fall ill with similar allergic symptoms!

Histamine and other amines are produced by bacteria from certain amino acids (can occur during production eg Swiss cheese or by spoilage). Particularly affects fish of the Scombridae family (viz tuna, mahi mahi, bluefish, sardines, mackerel, amberjack, and abalone) but can be any food containing the right amino acids and subject to the right bacterial enzymes.

Fish/shellfish/mollusc allergy

Allergy, Immunology,

Seafood as a term includes fish and shellfish. Shellfish isn’t the best term as it actually includes things without shells (octopus/squid, for example). Food labelling legislation refers to crustaceans (jointed things eg prawns/shrimp) and molluscs (which sometimes have shells, eg mussels/clams) but not well understood terms publicly.

But allergy to one does not imply allergy to the other! In fact, shellfish allergy is linked strongly to house dust mite allergy rather than fish, probably since they are all invetebrates with the same sort of Tropomysins.  Co-sensitivity is however relatively common (20-40% of fish allergic also allergic to shellfish) so must simply be atopic disposition!

Chordata (finned fish) subdivide roughly into bottom feeders, mackerel/tuna [perciformes] group, salmon/trout [salmoniformes] group and the rest (so called “bony fish”) but this doesn’t mean much in allergy terms.  The best studied allergen Gad c1, found in cod, is a parvalbumin.  These are found in muscle, esp slow twitch white flesh (cf dark muscled, fast fish eg tuna, swordfish).    At least 50% of those with allergy to one type of  fish will be allergic to another; there are no good predictors for this. Cod allergy typically means allergy to herring, plaice and mackerel but not great published evidence. Anaphylaxis UK and Allergy UK do not discuss cross reactivity at all (risk of cross contamination, of course). “White fish” is used as a grouping but doesn’t really have much biological meaning (and confusing because there is a N American white fleshed fish called whitefish…).

The rate of cross reactivity between different kinds of shellfish/molluscs is high since there is less variation in tropomysins.

Crustaceans includes crab, lobster, prawn, shrimp, langoustine. Most commonly eaten as prawn crackers or scampi. Molluscs include oysters, clams, mussels, squid, octopus.  Allergy to these is more common in countries where these are commonly eaten viz Spain, Japan – which is not surprising when you think about it, although typically surprising to the people who live there.

Sneaky places you find seafood:

  • Soups eg bouillabaisse
  • Pate
  • Seafood “crab” sticks – usually fish, not crab!
  • Worcestershire sauce (anchovy)
  • Pizza (anchovy)
  • Caesar salad (anchovy)

Reactions to seafood may not be allergic:

  • Anisakis is fish parasite, worldwide distribution, with a range of different allergens.  Larvae can cause immediate allergic response, but infection can also produce inflammatory symptoms of varying kinds, depending on where in the digestive tract the larvae are deposited.
  • Scombroid toxicity esp associated with salmon, tuna, mackerel.  Besides flushing, vomiting and wheezing, there can be severe headache and dizziness.  Onset is minutes to hours.
  • Ciguatoxin poisoning associated with reef fish eg sea bass, snapper.  Onset is slower – 30 minutes to hours, besides cramps, D+V there can be myalgia and paraesthesiae.
  • Shellfish (mostly bivalves) can be the source of a range of toxins with effects as diverse as paraesthesia, myalgia, ataxia, even seizures.   Mostly D+V though.

Cod IgE >20 gives 95% PPV, other cut offs lacking.  IgE>8 (>5 for salmon) predicts objective symptoms and non tolerance (cf partial tolerance).

Given importance of omega 3, unnecessary restriction should be avoided – Canning fish reduces immunogenicity, challenge?  Interestingly, many fish allergens seem to get MORE allergenic with heating, not less – Gad c 1 is known to become airborne in steam without denaturing! Various cases of fatal anaphylaxis simply to inhaling vapour of frying fish (aerosolised proteins, NOT smell, that causes reaction).

[JACI 2017 letter – small numbers though]

Food additives and allergy

Allergy, Dermatology, Immunology

Sorbic acid used as preservative.  Very low level of toxicity, as rapidly metabolized (a fatty acid).  A few reports of contact dermatitis and pseudo-allergy only.

Similarly with Tartrazine, MSG, Benzoate – in most children, there is very limited evidence for any role of food additives in causing non-allergic food hypersensitivity. Reactions may be more common in children with chronic urticaria and angioedema.  While other symptoms including migraine, gastrointestinal disturbances and arthralgia have been attributed to food additives, there are no reproducible and consistent data from DBPC studies to support this.

Natural additives eg Annatto can also cause problems in some patients!

Sulphites (sulfites, eg sodium metabisulfite) and natural salicylates may cause skin (usually contact dermatitis, but can be angioedema), GI, respiratory problems (even anaphylaxis) but these are best termed adverse reactions as they have a pharmacological basis.  Patch and IgE test available, however.  Very common in our food – in fresh foods to control browning, soft drinks, dried foods (as preservative), wine and beer.  Yet very rare in childhood and therefore hard to spot.  Also seen in in anaesthetic solutions, antibiotics, adrenaline (!!!), cosmetics.  Sulphites can have effects when used topically, orally or parenterally – mostly seen in those with asthma.  Can be acute or chronic.  Given the problem with using adrenaline, may need to be treated with steroids, antihistamines, bronchodilators instead! [Clinical & Experimental Allergy. 39(11):1643-51, 2009 PMID 19775253]  

Salicylates are a large group of assorted foods and other things that can cause problems including anaphylaxis.  Natural salicylates are generally acetylated so no need to automatically avoid them if intolerance to aspirin/NSAIDs.

[PJ Turner, J Paeds Child health 2010]

Pregnancy and nut allergy

Allergy, General paediatrics, Immunology, , , ,

No increased risk of peanut allergy with antenatal intake or intake during breast feeding, or with infant intake (Fox, J Allergy Clin Immunol. 2009 Feb;123(2):417-23). But did find dose response with household intake, esp peanut butter – so avoid!?

10 000 mums in US, not high risk, Eating Peanuts/Tree Nuts ≥5 times vs <1 time per month in their peripregnancy diet reduced risk of allergy by 2/3: odds ratio = 0.31; 95% CI, 0.13-0.75; Ptrend = .004). [Lindsay Frazier JAMA Pediatr. 2014;168(2):156-162. doi:10.1001/jamapediatrics.2013.4139]

60 000 mums in Danish National Birth Cohort, those eating peanuts and treenuts at least once weekly had kids with less asthma (OR 0.66), tree nuts also appeared to protect against rhinitis.

1200 US mums (not high risk) Higher maternal peanut intake (each additional z score) during the first trimester was associated with 47% reduced odds of peanut allergic reaction (odds ratio [OR], 0.53; 95% CI, 0.30-0.94).[J Allergy Clin Imm Volume 133, Issue 5, May 2014, Pages 1373–1382. DOI: 10.1016/j.jaci.2013.11.040]

Erythema multiforme

Dermatology, Immunology

Consists of well-circumscribed target-like lesions most commonly on the extremities. In about half of cases the cause is never found. Causes include:

Stevens Johnson Syndrome and Toxic Epidermal Necrolysis

Dermatology, General paediatrics, Immunology

Closely related. Characteristically severe, diffuse mucocutaneous eruption with atypical flat target lesions, irregular, possibly purpuric, blistering, even haemorrhagic! Painful, like sunburn.  Different pathology from Erythema multiforme! Evolve over 1-2 weeks, subside over further 2-3 weeks.

Other manifestations are fever (prodromal illness can manifest as URTI).  Mucosal lesions (stomatitis, conjunctivitis/blepharitis, or genital inflammation) accompanied by at least 1 other visceral organ, such as hepatic, renal, trach/bronchial or gastrointestinal involvement. Urethral involvement can cause retention of urine. Chest and abdominal signs pretty common!

Urgent ophthalmology – uveitis can lead to blindness.

Beer allergy

Allergy, General paediatrics, Immunology

Well described, mostly due to a non-specific lipid transport protein (LTP) so likely to find various co-sensitivities.  Some will be wheat, barley, maize, rice, yeast etc positive but history likely to be suggestive.  Consider hops, metabisulphites.  Malting, filtration etc probably affects allergenicity.  Presence of alcohol may enhance absorption?  In the case below, maize LTP eventually identified but patient could eat polenta and popcorn!

But individual beers vary in their allergenicity, and skin prick testing can reveal types that are safe! Hoegaarden in this report – Allergy 2012:67;1186