Category Archives: Immunology

IgA deficiency

General paediatrics, Immunology

Immunoglobulin A deficiency is the most common primary immunodeficiency.

1 in 700 healthy Western blood donors, but much rarer in some ethnic groups.  FH only in a quarter.

Defined as a serum IgA concentration of < 0.06g/L in patients over 4 years of age, with normal levels of IgG and IgM, which is not secondary to other causes e.g. myeloma.

IgA subclass (IgA1 and IgA2) deficiencies described. IgA deficiency may be found in ataxia-telangiectasia, and IgG subclass deficiencies, drugs (phenytoin, sulfasalazine), chromosomal abnormalities (esp chromosome 18), coeliac disease.

Sometimes seen in families as recessive trait, else dominant with variable penetrance.

Issues:

  • Infection – Most individuals with IgA deficiency are clinically asymptomatic. Otherwise, higher than usual frequency of respiratory (incl sinus) infections, and GI infections esp giardiasis. Recurrent infections more often seen when accompanying IgG subclass deficiency (so consider IVIG, although contains small amount IgA, so might produce antibodies).
  • Associated conditions – Long term follow up has found higher rate of gut and lymphoid malignancies. Increased frequency of coeliac disease, autoimmune disorders and allergy/atopy.
  • Blood transfusion – IgA deficient patients can develop anti-IgA antibodies to blood products (20-40%). But these antibodies also seen not uncommonly in normal population and do not help predict transfusion reactions, so testing controversial. Severe reactions are v rare (1 in >20,000 transfusions).
    • Enhanced surveillance for transfusion reactions recommended, and pre-medication with hydrocortisone/chlorphenamine should be considered.
    • If a patient has previously had a reaction, then plasma reduced products or IgA def donor products (best) recommended. However, danger of delaying transfusion must be weighed against potential risk.
    • Transfusion labs should be informed of patients with the diagnosis.

Pathogenesis of IgA deficiency is presumably abnormalities in Ig class switching. T-cell function normal in most. Possibly part of CVID spectrum?

J Clin Pathol 2001;54:337-338 pmid 11328829

Peanut immunotherapy

Allergy, General paediatrics, Immunology

In Scotland, now available at Glasgow Private Clinic – see www.peanutimmunotherapy.scot for more details.

More than 10 years ago, shown to be effective in children – 2014 Andrew Clark Lancet STOP II study – 39 children 7-16yrs, peanut flour orally.  2 weekly up dosing,  starting with 2 mg, increasing to 800 mg of peanut protein (5 peanuts) then maintained for total of 26 weeks.  Tolerance then assessed with challenge.

91% achieved final daily dose (although only 62% actually had negative challenge, which was to 1400mg, nearly double – and previous evidence has suggested that most people at this level can tolerate substantially more with only mild symptoms).

Side effects mainly oral itching (6% of doses), nausea, vomiting.  1 patient needed IM adrenaline (twice) for wheeze. Even minor reactions are annoying especially GI, or if daily!  And not always predictable.  Tend to get less over time, of course.  Paul Turner feels adverse event reporting “massaged” somewhat (no international consensus on reporting) – the word anaphylaxis not used except to thank the Anaphylaxis campaign, yet 22% of patients had wheeze at some point, even though reported rate of wheeze is 0.4% of doses. Still, anaphylaxis in hospital when potential reaction expected not the same as unexpected reaction in community.

Peanut IgE significantly reduced but not SPT! So works as long as you keep taking your daily dose, definitely side effects incl anaphylaxis, but not a cure.

No data yet on rates of reactions after treatment. But using anxiety model, OIT helps with “perception of severity” (as lots of minor reactions), “perceived ability to cope” (as managed already) and “rescue factors” (as more used to carry medicines).  Note how experience of using AAI seen as positive (and kids often laugh at anticlimax of it!). 1/3 of benefit of OIT seen after initial confirmation challenge, particularly where anaphylaxis occurred (and in patients as well as parents)! [Sarah Burrell, ADC 2021]

Roughly 10-20% don’t desensitize at all. A further 10-20% don’t achieve full dose.  And another 10-20% fail to achieve pass full dose challenge.  Benefit likely to be highest for those most at risk of anaphylaxis, yet tendency will be to cherry pick lowest risk cases…

AR101 Oral Immunotherapy trial (PALISADE) –  multiple authors including Jonathan Hourihane and George du Toit.  US/Europe, N=496 aged 4-17yrs.  Dose escalation then 24/52 maintenance (so about 12 months total) with peanut derived product, 67% passed 600mg peanut protein challenge (equivalent to 5-6 peanuts). [Some adult patients included initially but unsuccessful in all of them!]

Frequent mild/moderate events, but also in placebo group! 4.3% had severe events cf 0.8% of placebo group.  About 10% withdrew due to adverse events , mostly GI- interestingly another 10% were lost due to parents withdrawing consent, I wonder what their reasons were.

Michael Perkins NEJM editorial – possible risk of eosinophilic oesophagitis? Only 1 case confirmed.

[N Engl J Med 2018]

Second trial, just in Europe (ARTEMIS), n=227, up dosing every 2 weeks, just 12 weeks maintenance (300mg), so about 9 months treatment total.  58% tolerated 1000mg peanut (about 8-10 peanuts).  Again, lots of mild/moderate adverse events but in the controls too! 1% rate of severe in treatment group (1 patient).  10% withdrew due to adverse effects.  No eosinophilic oesophagitis reported. “Clinically important” improvements seen at the time of final food challenge in QOL scores related to “Allergen avoidance and diet restrictions” and “Risk of accidental exposure”, and in FAIM domains relating to perceived likelihood and chance of dying (both self and parent/carer reported) in the future.

Follow up study of self selected group of those who successfully completed 1yr PALISADE programme, who then opted to continue treatment for total of 18 vs 24 months – 48% of former still able to tolerate 2000mg, cf 80.8% of latter. Less adverse events over time of treatment, improved quality of life scores (“clinically meaningful”). Still peanut SPT positive (IgE a bit less for the 24 month group)!  There were more accidental peanut exposures in this study than in the original trial, suggesting less vigilance, but the severity of these reactions and need for adrenaline was low, which might confirm an immunomodulatory effect.

Another follow up study (ARC004, Vickery) looked at daily vs non-daily dosing (6 months twice weekly 300mg) after PALISADE. Non-daily dosers had 40% more adverse events, although 80% mild-moderate. Daily dosers had best evidence of desensitization – more than 70% passed 1000mg challenge with NO symptoms (better than PALISADE), and 69% of the cohort (“3A”) who did 2yrs plus could do 2000mg with no symptoms. Evidence of “ongoing immunomodulation” with extended dosing – IgE reduced, SPT did not.

Does not discuss whether non-daily dosing might be appropriate for subgroup who have best immune response to treatment.

ARC0008 study still to report (closed 2023), but provisional data reported show the trend towards decreased adverse events (AEs) at years 1 and 2 is maintained up to 5 years, with 94% of patients experiencing mild or moderate AEs and only 13% discontinuing PTAH use because of AEs overall.

Gastrointestinal symptoms were the most commonly reported treatment-related AEs. A downward trend in systemic allergic reactions was also reported. PTAH treatment resulted in reduced levels of peanut-specific IgE after the first year and increased levels of peanut-specific IgG4, with a lowered peanut-specific IgE:IgG4 ratio. A reduction in median peanut skin prick test wheal diameter was observed (11.50 mm at baseline vs 5.75 mm at year 5). Unpublished draft is available here.

Severe and uncontrolled asthma was an exclusion criterium, obviously. Similarly chronic/recurrent abdominal pain.

AR101 (Palforzia) has now received NICE approval for use in NHS England, which has set targets for patient numbers. In Scotland, SMC did not find sufficient evidence of economic benefit, which fits with ICER report (US economic review) 2019 which showed that peanut immunotherapy led to more systemic reactions and more adrenaline use with no cost benefit. But hard to quantify benefit of reduced anxiety and increased quality of life. Natasha trial currently looking at immunotherapy using commercial peanut flour across several UK sites.

Various forums about immunotherapy. One young person’s blog is Ask About My Peanut Allergy (stopped regular peanut!!! But doing well).

Future may be to combine different routes eg sublingual/patch.

Allergic Rhinitis

Allergy, General paediatrics, Immunology, Respiratory,

Under-recognized, particularly when chronic blockage (without itch/sneezing) rather than sneeze/discharge. Late phase reactions involving Eosinphil induction by T cells tends to produce chronic swelling and non-specific irritability eg cold air. Nose problems impact with everything connected eg eyes, sinuses, middle ear, lungs. Differential is wide eg CF/PCD, deviated septum, polyps.

ARIA= allergic rhinitis in asthma report (WHO).

Food protein–induced enterocolitis syndrome (FPIES)

Allergy, Gastro, General paediatrics, Immunology, Neonatology, Nutrition

Non–IgE-mediated severe gastrointestinal food hypersensitivity, typically presents in early infancy with repeated vomiting, dehydration, lethargy, metabolic acidosis (even mimicking sepsis).  Watery diarrhoea (sometimes with blood and/or mucus) can develop in some cases. The severity is really what makes it worthy of a distinct name, debatable if it is actually distinct from other non-IgE mediated food allergy.

Probably underdiagnosed.

A few unusual features cf type 1 allergy.

The most common offending foods are cow’s milk and soy in young infants; in older infants, there are a range of food triggers including some foods usually not considered allergenic eg rice, oat, chicken, sweet potato!  Egg an unusual cause in some countries!  Cases in breastfed infants have been reported, even severe hypotension requiring intensive care.

Acute symptoms occur 1 to 5 hours after ingesting the offending food.  Lasts up to 24 hours. Not always consistent, which might suggest co-factors important.

In Europe, rare to get multiple food FPIES but in UK/US/Australia about 25% (English speaking!?).

Diagnosis

Diagnosis is based, predictably for a non-IgE condition, on clinical history and food challenges. Leucocytosis and methaemoglobinaemia are associated but low specificity/sensitivity.  

2017 Consensus out of date but diagnostic criteria still used – 

  • Major – vomiting at 1-4 hours in absence of type 1 skin/resp symptoms.
  • Minor – at least 3 minor criteria eg second episode of repetitive vomiting after same food; extreme lethargy; hypotension; need for hospital care or IV fluids; etc

Probably mild, mod and severe! Proposed BIO-FPIES criteria includes abdominal pain, nausea, increase in neutrophil count (but 3 points for second episode of repetitive vomiting after same food).

Phenotype switching

Egg and nut FPIES often go on to develop IgE sensitisation (about 20%), less for others. Of those, about 30% of milk FPIES will switch to type 1 phenotype, 15% for egg, less for other foods. But overall, unlikely to make much of a difference to care (and doesn’t help predict resolution).

Management

No role for antihistamine/adrenaline!

BSACI has FPIES plan.

Family support at www.fpiesuk.org.

For introducing weaning foods, when known FPIES to one food, start with low risk foods, supervise common triggers eg rice/egg.

Challenge

Challenge is necessary to decide whether things are getting better or not. Consensus is that 12-18 months after last reaction is a good balance between chances of things being better, and risk of causing severe reaction.  

50% milk/soya resolve by age 3-4, more like 4-5 years for other foods. 

Traditional protocol is 0.3g/kg protein, divided into 3 doses over 30 mins.  But unrealistic for low protein foods eg fruit. And doesn’t really make sense to split dose when you don’t expect a reaction for hours (but risk of switch to type 1 allergy for egg/nuts).

2 day protocol (25% portion then whole portion next day) had less severe reactions. 

25-30% of age appropriate portion triggers reaction in most children. [Baked???] Over 50% react after at least 2 hours. 

Beaudoin 2024 has home challenge protocol but brave… 

[Marta Vazquez-Ortiz systematic review]

[BSACI FPIES grand round – Marta Vazquez-Ortiz (Imperial/St Mary’s, BIO-FPIES research network)] [2025 Shaker shared decision making] [2024 Anvari]

Urticaria

General paediatrics, Immunology

Or “hives” – itchy plaques or papules (weals), with surrounding flare, typical of histamine reaction in skin. Urticaria can also be accompanied by angioedema – although angioedema on its own may point to hereditary angioedema (else drugs eg NSAID, ACE inhibitors, oestrogens, statins), and absence of angioedema may suggest urticarial vasculitis, Schnitzler syndrome, cryopyrin associated periodic syndromes.

Not always allergy, although it is the classic rash of type 1 (histamine and IgE mediated) allergy.  Can be inducible or spontaneous.  Can be transient, intermittent or chronic (6 weeks minimum).

Burden on quality of life and health services can be substantial.

Inducible

Various kinds of physical stimuli can trigger urticaria, including:

  • Dermatographism – within 10 minutes of pressure
  • cf Delayed pressure type – tight clothing, sitting
  • Heat (including exercise and emotion)
  • Cold – can be secondary to autoimmune conditions or infection. Anaphylaxis risk from swimming!?
  • Sunshine (solar)
  • Water (aquagenic) – cold, hot, even rain…
  • Vibratory angioedema
  • Cholinergic urticaria
  • Contact urticaria

Can be mixed! Some tests have been suggested eg ice cube test (ice cube in a sealed plastic bag over the forearm for up to 10 min – wait for skin to rewarm), flannel test for aquagenic (wet towel for a few minutes on area of skin most affected).

Can be hormonal in girls, therefore cyclical (catamenial).

Differential

These things are considered to have different mechanisms:

  • Hereditary angioedema
  • Delayed food allergy eg alpha gal, or exercise induced
  • Atopic dermatitis
  • Chronic or recurrent infection (consider occult eg dental)
  • Erythema marginatum (as in rheumatic fever, but also a prodrome to HAE!)
  • Erythema multiforme
  • Drug reactions
  • Polymorphous light eruption
  • Thyroid disorders
  • Cutaneous mastocytosis
  • Systemic lupus erythematosus
  • Cryopyrin (autoinflammatory) disorders, typically with fever, arthralgia, eye inflammation eg Muckle Wells
  • Schnitzler syndrome – with monoclonal gammopathy
  • Gleich syndrome – with eosinophilia
  • Urticarial vasculitis (often spectacular, lasts more than 24 hours, bruising develops)
  • Autoimmune urticaria (caused by autoantibodies vs FC epsilon RI alpha, but antibodies do not correlate well with symptoms)
  • Mastocytosis and urticaria pigmentosa
  • Oestrogen, progesterone and pregnancy related dermatoses

And if everything else excluded, that leaves Chronic idiopathic urticaria.

Urticaria Activity Score available – wheals and itch over course of day, score 0-3. Moderate wheals are 20-50. Do for 7 sequential days and add up to give UAS7 score.

Diagnosis

Basophil histamine release assay and autologous serum skin tests suggested, 25% of all chronic urticaria patients are positive for one and/or other, but  50% are negative for both – so struggling for a diagnostic standard.

Essential:

  • FBC, CRP, ESR – CRP raised and eosinophils low in type IIb (mast cell-directed autoantibodies)
  • Total IgE – reduced in type IIb
  • Anti TPO antibody – high in type IIb (high ratio to total IgE)

After that, as indicated, eg:

  • ASOT
  • Immunoglobulin electrophoresis done in adults to look for paraprotein
  • H pylori – some have suggested eradication helps but BSACI come down against routine screening
  • TFTs, Functional autoantibodies eg Thyroid, ANA
  • Pseudoallergen (additives, flavourings, colourings) free diet for 3 weeks? BSACI not v keen
  • Tryptase – systemic mastocytosis? Not in BSACI guideline!
  • TTG – some case reports of association with coeliac disease
  • C3/4 – if suspected urticarial vasculitis, and if reduced, measurement of anti-C1q antibodies [BSACI urticaria guideline]. C4 low in HAE.
  • Cryoglobulins for cold induced
  • Biopsy – but for mastocytosis, bone marrow aspirate most sensitive!
  • Specific tests: ice cube, flannel, dermatographism, hot bath, exercise. 

Incidence of underlying cause varies regionally. And some of these things may simply be aggravating underlying spontaneous urticaria, rather than a cause as such!

Assess for co-morbidity – mental health, autoimmune disease, allergy.

Treatment

Identify triggers – drugs (esp NSAIDs), foods (high histamine, pseudoallergens?), stress, infection.

For acute, non-sedating antihistamines (H1 blockers), else steroids. Evidence for H2 blockers eg ranitidine very weak.

For chronic, continuous non-sedating AH effective in <50% of patients. No evidence that one antihistamine is better than any other. Guidelines recommend up to 4x updosing (studies support for cetirizine, fexofenadine, otherwise desloratadine, levocetirizine, rupatadine!). 

No evidence that using different H1 blockers at the same time has any advantage (moderate consensus only, however…)

Weak evidence for steroids! Suggests maximum 10 days. Similarly montelukast.

Omalizumab is second line for both spontaneous and inducible – monthly SC injections 300mg (not dependent on IgE, as is asthma dosing) every 4 weeks (safety data now from age 1). Increase dose or shorten interval if necessary (up to 600mg every 2 weeks). After that, ciclosporin.

Other treatments with limited evidence include doxepin, ranitidine, methotrexate, dapsone etc. 

Tranexamic acid for angioedema?

No evidence for thyroxine treatment if autoantibodies, if euthyroid.

Plasmapheresis and IVIG have been used…

Tolerance to triggers can be induced (rapidly in some cases, eg within days), but not usually v pleasant, and temporary only…

Note the high rate of anxiety, depression, somatising disorders (50%).

[EAACI/GA2LEN 2021]

Primary C3 complement deficiency

General paediatrics, Immunology

C3 is the major complement component.  Associated with bacterial infections esp gram neg eg Meningococcus, Enterobacter, Haemophilus, E coli.  Gram pos infections also seen.  Some increase in autoimmune eg SLE but this is more well recognized with C1q, C2 and C4 def.

Secondary C3 def seen with nephritis (complement activation products in kidney), but also with hereditary factor I and H deficiency (cofactors in C3 product cleavage).

Immunodeficiency

General paediatrics, Immunology

Age of child and type of bugs found important.  SCID and severe DiGeorge can present in first few months of life (failure to thrive, chronic diarrhoea, recurrent viral infections, thrush). Antibody defects tend to present in later childhood; neutrophil problems in between (which goes to show how good your innate immunity is).

On average, a young infant will get 5-6 resp infections per year; if day care + older sibs that goes up to 12/yr.

ESID diagnostic protocol is not particularly simple but does help by starting with clinical presentations. [Clin Exp Immun 2006; 145:204]

  • Family history (including autoimmune disease eg SLE, arthritis, thyroid, vitiligo, endocrine glands)
  • PMH of 2 invasive, or 1 invasive plus many minor infections
  • Lymphopenia: at least 2.5 in baby or infant as rule of thumb.

Age of Presentation:

  • Under 6 months: SCID, T cell (DiGeorge, Chronic Mucocutaneous Candidiasis, Wiskott Aldrich)
  • 6 months to 5 yr: ataxia telangiectasia, antibody disorders
  • Over 5 yr: specific antibody, complement disorders

Typical bugs:

  • Bacteria – if gram positive or Haemophilus, think antibody or complement disorder (or SCID, of course). Plus:
    • Staphylococcus – phagocytic (eg Chronic granulomatous disease)
    • Meningococcus – properdin disorder
    • Pneumococcus – spleen, ectodermal dysplasia, IRAK4 deficiency
    • Enteric bacteria – phagocytic, SCID
    • Salmonella – cellular or phagocytic disorder
    • Listeria – SCID
  • Viruses – think cellular or SCID, esp CMV and other herpesviruses.
    • HSV – Ataxia Telangiectasia! Mollaret’s meningitis is recurrent chronic meningitis due probably to HSV
    • Enteroviruses – antibody disorder
    • Warts – DOCK8 (with eczema, also molluscum)
  • Fungus – which fungus helps you know what the problem is.
    • Aspergillus commonly seen in CGD, in fact CGD appears to be the only condition where lung aspergillus is seen, and A nidulans v specific for CGD).  Whereas candida rarely a problem in CGD unless neonate or heavy steroids for colitis! Rarely in SCID (other bugs out compete!). Having damaged lungs however can create potential for aspergillus infection in other immunodeficiencies eg Hyper IgE.
    • Candida on the other hand is often seen with SCID. Also autosomal dominant Hyper IgE syndrome (also eczema, pneumonia, skin abscesses), and then a range of conditions where it is the main feature:  IL 17 (recruits neutrophils) and IL 23 (pathway includes STAT3, AIRE, DOCK8, CARD9). CARD9 classically associated with CNS infection but now cases of invasive moulds. AIRE associated with autoimmunity viz APECED (see below).
    • Invasive fungal disease also seen in severe congenital neutropenia and Leucocyte Adhesion Disorders but they usually get severe bacterial infections first!  Functional assays can guide treatment eg IFN.
  • Cryptosporidium – CD40 ligand
  • Pneumocystis jiroveci – SCID, CD40 ligand, phagocyte disorders, ICF (= Immune dysfunction, Centromere instability, Facial dysmorphism; actually a humoral defect. Due to DNA methylation defect hence bizarre chromosomes).  Not just HIV!
  • Toxoplasma – SCID
  • Mycobacterium incl BCG – cellular and phagocytic disorders
    • IL12, IL23, IFNgamma, and STAT1 disorders – various defects identified, which explain about half of all atypical infections. But these defects have low penetrance, rarely disseminated BCG or TB. Multifocal mycobacterial osteomyelitis and granulomata seem to be particularly troublesome though in those with otherwise mild disease. Also susceptible to salmonella, listeria, CMV and other herpesviruses. NOT staph, aspergillus, burkholderia.
    • NEMO (NF Kappa beta Essential MOdulator) defects affect all manner of nuclear activating cytokines, so are not very organism specific; gram positives or negatives, PCP, CMV, mycobacteria all more likely. Strangely, aspergillus does not appear to be a major problem! Null alleles are lethal so always hypomorphic. X-linked, females sometimes affected if mosaic, so look for incontinentia pigmenti.
  • RSV – HIV!
  • Chronic recurrent multifocal osteomyelitis = a clinical diagnosis, inflammatory not infective! Self-limiting, rarely persistent bony abnormalities.

Other clinical problems:

  • Cardiac – Digeorge
  • Eosinophilia and eczema – Hyper IgE, IPEX, Wiskott Aldrich, DOCK8
  • inflammatory bowel disease – CGD, IPEX, CVID, CD40 ligand.
  • Rash in SCID (=GVHD)
  • Liver abscesses – 50% will have CGD in UK.
  • pneumatocoele – Hyper IgE
  • Absent thymus on CXR (pleurae appear to meet in middle) – DiGeorge, SCID
  • Bruising/bleeding – Wiskott Aldrich
  • Abnormal nails, hair, teeth (eg conical incisors), skin (erythroderma), sweat glands – Ectodermal dysplasia, or Cartilage-Hair (= immune osseous dysplasia, due to RNA processing defect, short limbed dwarfism, variable combined defect esp human herpesviruses. Predisposed to lymphoma). X-linked recessive anhidrotic type ectodermal dysplasia presents early in life, but NEMO defects found with abnormal teeth alone (see above). Often get surprisingly little inflammatory response with infections, at least milder ones.  Also APECED (just candida).
  • Coarse facies – Hyper IgE, esp extra/irregular teeth, ICF, but lots of other syndromes of course
  • Persistent vaccination nodule – CGD!
  • Albinism – Chediak Higashi (patches in retina or skin) and related. Incontinentia pigmenti suggests mosaicism, so girl may have X-linked disorder.
  • Late walking, unsteadiness, drooling – ATA (telangiectasia later, esp eye)
  • Diplegia/dysarthria – PNP def
  • Bird head – DNA repair defect (like Seckels, developmental delay)
  • Erythrophagocytosis/lymphoma/aplastic/persistent EBV – X linked lymphoproliferative disorder
  • Late cord detachment = neutrophil or leucocyte adhesion defect
  • Autoimmunity – CVID, CD40 ligand, APECED (ectodermal dystrophy, chronic mucocutaneous candidiasis), IPEX (enteropathy, x-linked)
  • Cytopenias – ALPS, DNA repair and autoimmunity in CD40 ligand.
  • Granulomas – CDG, CVID

History

Consanguinity.

Examination

Scars, nails, creases.

Tests

Always test for HIV!

IgG will be maternal in first 6 months of life.  IgM reaches adult levels in toddlerhood.  IgG in young childhood.  IgA only in adolescence – often low in young children, deficiency only diagnosed after age 4.  Immunoglobulin levels can be high in HIV, Digeorge, CGD.

IgG subsets are controversial – not great evidence that they are responsible for increased infections. High IgM can indicate a problem with class switching eg Hyper IgM syndrome.

Lymphocyte counts:

Total Lymph count (5th centile) Age
2.9 2-3/12
3.6 4-8/12
2.18 12-23/12
2.4 2-5yr
2 7+yr
(Comans, JPed 1997;130:388)

Functional abs – pneumo often worse response esp polysacch.

Subsets – EDTA, fresh, room temp (else CD4 drops – “fridge AIDS”).   CD3 are T cells, which then subdivide into CD4 and CD8 T-helper cells. CD19 and 21 are B cells, CD56 are NK cells. CD4 numbers should exceed CD8 – reversed ratio seen in HIV. A specific NK problem has been described with increased susceptibility to herpesviruses and papillomaviruses. Abnormal NK numbers also seen in Chediak-Higashi, CD40 ligand and NEMO (?).  Low CD4 seen in steroids, sepsis, Digeorge, CVID, Ataxia telangiectasia, Coeliac.

If subsets normal, look at proliferation studies (signalling problem rather than maturation problem).

A total hemolytic complement (CH50 or CH100) screening assay looks for defects in the complement pathway. AH50 or AH100 tests the alternative pathway. [C3/C4 are not enough!]

[Peds 11.127.810]

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.