Category Archives: Immunology

Venom immunotherapy

Allergy, General paediatrics, Immunology

Pharmalgen® no longer available. Alutard is an option (but no SMC submission) for the treatment of IgE-mediated bee and wasp venom allergy in those who have had [www.nice.org.uk/TA246]:

  • a severe systemic reaction to bee or wasp venom;
  • a moderate systemic reaction to bee or wasp venom PLUS:
    • a raised baseline serum tryptase concentration,
    • a high risk of future stings,
    • or anxiety about future stings.

Comes as an initial treatment set, with graded doses, plus a maintenance set.  For treatment, start with subcut at 1000th of SPT threshold dose or 10th of intradermal threshold, increase every 3-7 days until a threshold is reached.  Rush or modified rush regimens also available.  Then maintain maximum tolerable dose (typically 100mcg)  at 4 weekly intervals initially, gradually extending, for at least 3 years.

If symptoms or signs of hypersensitivity to therapy develop (e.g. rash, urticaria, bronchospasm, faintness), even if mild, the child should be observed until these have resolved completely. [BNFc] High baseline tryptase may make reactions to immunotherapy more likely – but still appropriate to do.

Asthma is not a contraindication but severe asthma (specified as FEV persistently below 70% despite treatment) is.

No age cut off, but data “sparse” for children under 5.

Some patients tolerate venom immunotherapy well but still have systemic reactions! So challenge tests with subcut venom not reliable – use live insect! Done sometimes to identify candidates for immunotherapy, or to identify those on maintenance immunotherapy to see who is not yet protected esp at high risk of sting or high risk of fatal reaction.

Efficacy of immunotherapy is related to adherence to treatment!  High adherence at 5 years to subcut immunotherapy.  Recent contraindications more flexible than previous ones.  [Pitsios, Allergy 2015;70:897]

Venom immunotherapy is 95% effective against wasp, 80% against bee.  Consider VIT if mild reaction but high tryptase, high risk of sting or major QOL issue.  But kids have better prognosis so only VIT for most severe.  Don’t do VIT without positive test.  Usual duration of VIT in UK is 3 yrs.

Cow’s milk protein/allergy intolerance

Allergy, General paediatrics, Immunology, Nutrition

A common issue for babies and infants.  But not that common – in EAT study, symptoms (vomiting, colic, eczema) related to milk reported by 13% of parents, but only found in 0.7%!

“Intolerance” suggests that cow’s milk causes adverse effects (generally gastrointestinal) but without committing to an underlying mechanism. 

If there is reason to think the adverse effects are immune mediated (because there are signs/symptoms outside the GI tract, for example) then it is preferable to use “cow’s milk allergy” (which then divides into type 1, non type 1, or mixed). 

Can even affect exclusively breast fed infants if sufficient milk proteins transmitted in breast milk, but probably over diagnosed (as challenge after 2-4 weeks not done).

Not the same as lactose intolerance – lactose is a sugar, intolerance to it is due to malabsorption and effects of undigested sugar in colon eg bloating, diarrhoea.  NOT rash, vomiting.  Usually post-gastroenteritis, transient.  No useful test other than lactose restriction for 2 weeks then rechallenge.

Some parents feel milk leads to more respiratory problems – there is some evidence that milk allergy is associated with more respiratory/GI infections and that an elimination diet (although supplemented by pre/probiotics) lead to reduced infections and less antibiotic use.

Cow’s milk allergy

Can be IgE mediated (immediate, histamine release, potentially anaphylaxis), else non-IgE mediated (typically more chronic, delayed symptoms, predominantly gastrointestinal, possibly a threshold level below which a patient is asymptomatic) but can be both. Non-IgE mediated symptoms include:

  • Eczema
  • Colic
  • Gastro-oesophageal reflux
  • Constipation [NOT green or mucuous stools]
  • Eosinophilic oesophagitis
  • Allergic Proctocolitis (FPIAP – see below)
  • Growth failure
  • Enterocolitis (FPIES)
  • Enteropathy – no blood, and longer recovery time (weeks)

Note that the first 4 problems are very common and cow’s milk protein intolerance may only be a factor in a small proportion of such patients. Best predictor of whether symptoms are due to milk allergy appears to be the background of the health care professional, not the history, age or family history of atopy! See Imperial College review of evidence (Munblit and Perkins 2020).

ESPGHAN 2023 guidance does detail trial of exclusion for reflux. For colic, very strict – only when Rome IV research criteria satisfied (3hrs per day, without obvious cause, cannot be prevented or resolved by care givers, 3 days a week, confirmed with prospective diary) AND suspected on basis of additional symptoms.

In patients with eczema, a mixture of IgE mediated and non-IgE mediated reactions can be seen (and immediate reactions may be seen on re-introduction even when only delayed reactions seen initially).

Food protein induced allergic proctocolitis

Well baby with blood +/- mucus in stool, usually in first few weeks of life. Associated with eczema and family history of food allergies. Mixed feeding appears to protect. Benign – in exclusively breast fed infants, ESPGHAN says no dietary intervention for first month. Even for formula fed babies controversial, as large study in Boston found elimination increased risk of later type 1 milk allergy by factor of 5!

DRACMA 2022 guidelines from WAO quote small Brazilian study showing 80% tolerant by 6 months so earlier reintroduction presumably possible if you do exclude. Calls for more research.

So depends on severity/frequency – and if you eliminate, definitely challenge early.

Diagnosis

Prescriptions for specialist formulas increased massively in early part of century – 10-12x higher than expected in England, for example. Estimated prevalence is 1% in the UK, less than 0.3% in Germany and Greece.

With delayed reactions, diagnosis depends on history, and then dietary exclusion followed by re-challenge after 2-4 weeks. In the case of FPIES, re-challenge may need to be done in hospital. Sometimes the diagnosis is only made at endoscopy.

Dietary exclusion has been shown to affect long term taste preferences. Also significantly restricts diet, with potential impact on calcium intake (and also riboflavin, niacin, zinc).

For immediate reactions, skin prick testing (SPT) more specific than IgE blood testing. 3mm SPT wheal considered positive in infants, but low specificity; when doing IgE/SPT tests, also check egg allergy (high cross-reactivity) and soy (for formula substitution). If IgE/SPT negative, needs challenge (ideally double blind).

Substitute Formulas

  • Breast feeding mothers may need to exclude dairy in their own diet.  Daily requirement of calcium (1250mg) and Vitamin D (10mcg), so supplement and fortified alternative dairy products needed.
  • Because of theoretical risk from phyto-oestrogens in soya, use extensively hydrolysed formula (EHF) instead of soya formula if under 6 months. Soya cross reactivity is reported in up to 25% of young infants with non IgE allergy but this varies widely. Soya milk usage is also associated with increased risk of subsequent peanut allergy (RR=2.6)!
  • ESPGHAN says you can also use hydrolysed rice formula – available in UK? Reported arsenic values are within WHO limits.
  • About 10% of infants will not tolerate even extensively hydrolysed formula (eHF) and may require an amino acid based formula; anaphylaxis has been described even with hydrolysed formula.  AA formula should be used first line if:
    • anaphylaxis,
    • severe non IgE (eg PR bleeding leading to haematological disturbance, severe skin disease, FPIES),
    • faltering growth (says ESPGHAN but controversial).
  • eHF potentially better than other types of formula, and potentially added benefit from probiotics – in trial of N=260 (42% IgE mediated, non-randomised) tolerance after 12 months 79% for EHF & Lactobacillus rhamnosus GG (LGG), cf 43% for EHF. 23% soya, 18% AA. Associated with IgE mechanism (negatively, OR 0.12), and EHF (4.41) or EHF & LGG (29) [Canani, European lab for food induced diseases, Naples. PMID 23582142].

Challenge

Cow’s milk must be tried again to prove it is the causal agent, unless type 1 symptoms, or severe non-type 1 (FPIES).  If symptoms return then continue elimination diet for at least 6 months, else 1yr of age, then re-introduce gradually. ESPGHAN says do IgE for milk first if type 1! Highlights that boiling more likely to hydrolyse proteins than baking, but ignores matrix idea. No evidence for further challenges but suggests every 6 months.

Prognosis

Exposure does encourage tolerance. In studies, after 6 months of oral desensitization, 11% had had positive food challenges cf 40% for abstainers. And in the abstainers, the threshold of sensitivity tended to be lower, and symptoms more severe [Eur Ann Allergy Clin Immunol. 2007 39:12-9. PMID 17375736].

Almost all non IgE milk allergy and most type 1 resolves by 1yr after diagnosis.

Reintroduction is typically done according to a “ladder” of 4 or more steps – baked milk, then boiled milk, then yogurt, then fresh raw milk. Baked milk is less allergenic due to the matrix of wheat – if wheat allergic, then gluten free cheese oatcakes (Nairns) or shortbread (Walkers/Asda).

IgE disease less likely to resolve if asthma, rhinitis, severe reactions or strongly positive results.  Median age of tolerance 5yrs.  According to Thermofisher, positive IgE Casein (Bos d 8) means less likely to tolerate baked milk or outgrow, as protein (casein) more heat stable (no consensus on component testing in ESPGHAN 2023).

You could argue for early introduction of weaning foods but this is only briefly mentioned in ESPGHAN 2023 and not yet recommended.

Final adult height has been shown to be reduced in milk allergy – this could be related to co-morbidities (asthma, eczema, steroid use, sleep disruption etc) or feeding difficulties (associated with elimination diets).

Prevention

EAACI task force recommends against use of milk formula top ups in first week of life in breast fed babies. Low certainty, though. Also recommends avoidance of allergens (including milk but not limited to) in pregnancy and during breast feeding!

ESPGHAN discusses too. In a multivariate model, independent factors associated with milk allergy were family history of allergy (OR = 2.83), avoidance of dairy products during pregnancy or breastfeeding (OR = 5.62), and formula given at the maternity hospital (OR = 1.81). In an RCT of daily 10ml formula supplementation (n=504 breast fed) cf only soya formula if required, performed between 1 and 2 months of age, daily formula ingestion prevented nearly 90% of later milk allergy confirmed by OFC at 6 months (RR: 0.12). EAACI neutral on this – and regular top ups would never be supported by breast friendly clinicians. Overall however, ESPGHAN group decided there was insufficient evidence for any of these things.

See also EAT study, and GINI study.

Treatment

66% of kids grow out cow’s milk allergy, even if they completely avoid it. But rate rises to nearly 90% if baked milk introduced. And less restrictive diet good for everyone, of course.

Salmivesi RCT from Finland 2012 – n=28, age 6-14. 81% using daily milk 6400mg protein at 12 months. First dose milk 0.06mg – 8 further observed doses (0.12mg day 8; 0.24mg day 15; 2.0mg day 36 [big jump!]; 4.0mg day 38 [2 days later!?]; 8.0mg day 42; 40mg [big jump again!] day 57; 80mg day 64; and 160mg on day 78) with other dose increases done at home. Monitored for 2hr in clinic. Final dose of 6400mg (=200ml) was given at home (!) on day 162.

Oral immunotherapy (OIT) for severe milk allergy (IgE >85 or low eliciting dose):  at 1yr 36% tolerated 150ml, 54% 5-150ml (good enough for accidental exposure). 10% could not complete protocol. [reference?]

DRACMA update on milk immunotherapy (2021) mostly fresh milk used in research. Randomized trials looked at kids aged 2-14, mean 8. Non randomized had wider range. 67% tolerated 150ml (cf 2.2% of controls), 78% tolerated 5-150ml (=swig protection) (cf 3.3% of controls). Anaphylaxis rate of 5.5 per person-years (although not always defined, and not always usual definition). 63% used IM adrenaline!?

6.9% developed EOE but rarely biopsy confirmed. No deaths.

2–8 weeks after discontinuation of successful OIT, tolerance of cow’s milk persisted in only 36% (20%–91%). So you have to persevere life long, probably.

Quality of life badly reported – only 5 studies. 1 study found parents reported better QOL in 37%, worse in 26%, and unchanged in 38%! 2 conference abstracts reported improved QOL or at least reduced anxiety in general and reduced fear of unexpected reaction. Some studies found worse QOL! Certainty of evidence overall v low…

Only 1 trial and 2 non randomized studies of baked milk OIT! In the 1 RCT of baked milk, 73% achieved tolerance at 12 months (cf none of control group) – other studies did not find evidence of effectiveness however (meta-analysis of Anagnostou. Tolerance to heated or baked milk may be temporary and diminish within a few years. Dantzer. 20% required adrenaline! Only some children assessed for QOL, with evidence of benefit – of the parents studied, no improvement in QOL! [Dantzer and Dunlop 2021]. Low desensitization rate for unheated milk means persisting concern about exposure in real life despite less frequent adverse reactions (8%–33%).

Other studies did not find this relationship, which is consistent with the meta-analysis results of Anagnostou et al. (41). Tolerance to heated or baked milk may be temporary and diminish within a few years. Dantzer et al. found that a protocol involving gradually increasing doses of baked milk was effective in promoting desensitization (73% achieved end dose of 4000mg cf 0% of controls).  Mean age 11. “This suggests that the initial dose [and then building] may influence the efficacy of desensitization.” 

[Yan Wang, China – Front. Immunol., 04 June 2025]

4% rate of biopsy proven EOE – note EoE typically emerges approximately 2.8 years after initiating the maintenance phase so many studies will miss…

Longer duration better. None of the studies reported on sustained unresponsiveness.

Only Dantzer study reported quality of life! 

Highlights “a dire need for a standardization in outcome assessment and reporting,” and that successful completion of OFC needs to be validated as a predictor of “real world” success. [Natasha trial will hopefully clarify further…]

Separate article on OIT recommendations – apart from balancing risks and benefits, recommends using omalizumab (monoclonal anti-IgE) in advance and in initial stages of oral immunotherapy with unheated cow’s milk. Inferring from limited evidence (use in other food allergies, mostly) that risk of anaphylaxis reduced (RR0.34 but not significant!). Not really any downside? (But costs at least £256 per dose, maybe double? Lasts a month?). Plus, does not recommend baked milk OIT as very low certainty of benefit. More evidence on effect, risks, QOL benefit obviously required.  

Sublingual/epicutaneous immunotherapy (SLIT) for milk? Not much evidence – low rate of success and high rate of relapse.

[EGPHAN 2023, Frontiers in Pediatrics 2019; BMJ cmpa article sept 2013]

Rush study from Japan used microwaved milk – microwaved for 100s at 550W (!). Dosing was 2–4 times a day in hospital for several days (frequent adverse events) aiming for 200 mL dose (total daily, I assume). If not achieved, dose increases changed to 1ml per day. At 200ml, dosing changed to once a day. After 2 months of maintenance, length of time in the microwave gradually reduced.

Another Japanese study looked at using heated milk powder (3 mins at 125degC) vs unheated milk. Rush protocol (5 days in hospital) up to maintenance of just 3ml daily. At 1 year, 35% and 18% in the HM group and 50% and 31% in UM group passed the 3 and 25 mL OFCs, respectively, so not great efficacy. Rates of moderate or severe symptoms significantly lower (halved) in the heated milk group however.

Natasha Trial is looking at Peanut or cow’s milk OIT in UK – groups are Peanut age 6-23yrs, Peanut age 2-3yrs, Cow’s milk age 3-23yrs. Using everyday food products. Final results expected 2027.

LEAP-On study

Allergy, General paediatrics, Immunology

Follow-up from LEAP study, after both groups (eating and avoiding) told to avoid peanuts for 12 months. The rate of adherence to avoidance in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% [52 of 280 participants] vs. 4.8% [13 of 270].

[George du Toit, Gideon Lack in London, DOI: 10.1056/NEJMoa1514209]

Legume/pulse allergy

Allergy, General paediatrics

Legumes, pulses, beans…  Some terminology first: legumes are plants in family Fabaceae (or Leguminosae).  Pulses are (strictly) those cultivated for DRY seed, as opposed to green beans, broad beans etc that are eaten fresh.  Lentil simply describes shape (“like lens”).  So other examples of legumes are peanut, lupin, tamarind, carob, alfalfa!

Very common cause of food allergy, even excluding peanut! And varies across different cultures, depending on typical pulses used.  Fifth most common cause of food allergy in Spain.  In India, often a trigger of asthma/rhinitis when being boiled.  Cross sensitivity is seen, but not automatic, and hard to predict.

Soya allergy is sometimes seen in highly atopic babies, but otherwise actually pretty rare (except in Japan) – lucky, cause gets into lots of different things eg many breads.  Soya lecithin is a common additive, used to make texture more smooth, but usually only in very small amounts. Fermentation eg soy sauce appears to significantly reduce allergenicity, soya flour also seems less allergenic than soya milk, even though most of the allergens are cupins eg 2s albumin and would therefore be considered heat stable.

Lupin is used in some continental baked goods, for example packaged waffles.  A good proportion of peanut allergic children will be allergic to it too, but as lupin is not found very commonly most will never know or have a problem with it. A few restaurants (in UK and abroad) have lupin in their allergy menus.

A couple of lentil allergens have been identified including a vicilin and a lipid transfer protein.  In my experience pappadoms can often be tolerated – there is certainly evidence that autoclaving for 30 mins can affect binding, but these are only deep fried for a few seconds.

Both the known pea allergens are vicilins, hence cross reactivity with lentil.  Chickpea allergens however are not (one a prolamin, the other a cupin) – still, cross reactivity fairly common.

French beans have an LTP so potentially severe, and potentially fruit allergies too.  Green (mung bean) and red gram are cupins, black gram appears to be something else.

[Clin Rev Allergy Immunol. 45(1):30-46, 2013 Aug]

Angioedema

Allergy, Clinical, Common, General paediatrics, Immunology

Swelling, usually acute, non-pitting.  May be erythema too.  Typically affects face, especially lips, tongue, eyes, but can be limbs, even internal!

Usually related to urticaria (wheals). As with urticaria, can be allergy – clue is consistent trigger, pattern of recurrent episodes – but can have other causes.

Angioedema without urticaria – consider hereditary or drugs, especially NSAIDs and ACE inhibitors.

Autoimmune Hepatitis

Gastro, General paediatrics, Immunology

Presents with anything from subtle anorexia, fatigue, rashes, abdo/joint pain to acute liver failure.  Jaundice does not relate to degree of histological fibrosis.

Check Prothrombin time, glucose, ammonia, lactate to monitor liver disease. Response to Vitamin K at 8 hours is prognostic, so refer to specialist centre if poor.

Type 1 (60%) is ANA/SMA (=small muscle) positive, usually presents as a viral hepatitis ie jaundice, raised transaminases, but can present insidiously, even with established portal hypertension, or as acute on chronic. Type 2 is LKM1 (liver/kidney/microsomal) positive, similar clinical presentation but probably more jaundice and cirrhosis, less impairment in synthesis. Seronegative hepatitis has been described in up to 20%.  Antibodies to soluble liver antigen described.  Quite common to see pANCA, too (not sensitive or specific).  The role of these autoantibodies in disease is unclear!

As with other autoimmune diseases, strong association with HLA types.  DR4 associated with less severe disease, lower rate of relapse (but older presentation).  Has been reported in association with immune disorders eg autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

Alkaline phosphatase rarely exceeds 4x normal and generally remains less than 2x normal. Raised immunoglobulins are a clue, with a selective increase in IgG (up to 3x higher than the upper level of normal) seen in 75-85% (kids and acute less likely).  But not specific – also seen in Wilson’s disease; other causes should be excluded too. Interface hepatitis on biopsy, with sharp differentiation between inflammatory zone and normal liver tissue.  Findings don’t always match biochemistry.  Nonetheless, diagnosis is ultimately clinical!  Diagnostic scoring system available.  Differential also includes chronic hepatitis C and drug induced liver injury.

Treat with steroids, azathioprine (remember TPMT polymorphisms)  when improving, else mycophenylate. 85% achieve remission, biochemically within 6-12 weeks, histologically 6-12 months.  More than double normal enzymes is an indication for treatment, else bridging or multilobular necrosis.  Progressive fibrosis is associated with liver inflammation, and poor response to treatment (inability to suppress inflammation within 12 months) is associated with progression to cirrhosis (54%) and transplantation (15%).  But fibrosis can be stopped or slowed in the majority, and even cirrhosis can regress with treatment.  Aim is normal transaminases, immunoglobulins, histology – biopsy is still gold standard for assessing fibrosis.

Unlikely to outgrow.  Some trials of withdrawing treatment after remission, only a minority manage more than a year without relapse.  Azathioprine 2mg/kg daily effective.  Ciclosporin and MMF are second line agents.  Hepatobiliary cancers and lymphoma risk is increased and should be screened for.

Transplant may be necessary eg severe acute presentation with poor response to treatment.  Results are good, recurrence is rare but well described.

Variants

Can be features of other disorders eg primary biliary cirrhosis, primary sclerosing cholangitis.  Biliary changes are commonly seen in autoimmune hepatitis in any case.

Can be part of polyendocrine syndrome type 1.

[Heneghan, Lancet 2013; 382: 1433–44 http://dx.doi.org/10.1016/S0140-6736(12)62163-1]

See also PMID 22495399

Testing for antibiotic allergy

Allergy, General paediatrics

See also Penicillin allergy.

Systematic review – just 0.21% of unselected general paediatric outpatients exhibit positive antibiotic allergy tests, and only 6.8% of those with suspected allergy test positive.

No evidence to support using skin prick testing.  Intradermal testing has high false positive rate (64-67% for penicillin and clarithromycin). Caubet did oral provocation test (OPT) regardless of intradermal result to beta lactam, NNT=11 to avoid one OPT! [Ped All Immun 2015 ]. OPT reactions tend to be cutaneous and mild, usually more than 1hr post administration.

Where reaction is severe but non-immediate, eg Stevens Johnson syndrome, Toxic Epidermal Necrolysis (TEN), Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), care needs to be taken with investigation, but studies have reported intradermal and OPT without unsafe adverse effects.  If reaction is anaphylaxis with first dose, then OPT contraindicated.

Wide variety in regimens.  Suggests 1-5 incremental doses of amoxicillin for mild reactions (timing not specified), giving cumulative dose appropriate to child, then continuing for 3 days.  Skin testing may be appropriate for severe reactions according to risk:benefit balance.  Check asthma well controlled, no antihistamines.  Warn that low risk of false negative result (absent co-factors) and low risk of re-sensitization.

Intravenous provocation only where PICU!

[Marrs, ArchDisChild 2015]

Macy article says any rash can have OPT! 5mm pos SPT for penicilloyl-polylysine has good negative predictive value for anaphylaxis with OPT. Recommends 5 days amoxicillin.

[Ann Allergy Asthma Immunol 121(2018):523−529]

Mirakian article suggests SPT for all immediate reactions! Split dose challenges, with a week between first and second doses!

For non immediate reactions (1-72hrs), OPT confirmed in 59%, ID less than 40%.

6 studies showing that benign reactions (ie witnessed macpap or urticarial, no pain/burning, <50% skin surface etc) do not need skin testing.  Geneva have done more than 800 straight to OPT.  New EAACI guidelines in press.

If delay in reaction is unclear, assume immediate.  SPT vs amoxicillin, PPL, MDM.  IgE vs BPL.  0.04ml ID volume.  Note different reference ranges!  See Brockour, Allergy 13

Recent letter claimed OPT after skin test was “unnecessary, dangerous, unethical”!  But 30-100% false negatives!

Clavulanate allergy described.

Test sensitivity falls more than 4/12 after episode, ideally do within 4-6/52????

Basophil activation test using flow cytometry looking promising for IgE mediated drug reactions.  EAACI interest group working on Drug Allergy Passport.

Henoch Schonlein Purpura

Common, Dermatology, General paediatrics, Immunology, OPD, Renal, Rheumatology

or HSP. Usually preschool but any age! Boys more than girls. Vasculitis, leucocytoclastic with IgA predominance. EULAR criteria 2010.

Features:

  • Urticarial rash becoming purpuric but still raised (pathognomic), predominantly on lower limbs, especially extensor surfaces incl buttocks, but sometimes trunk, rarely face (infant).  Accompanying soft tissue swelling, as seen in photo in feet.
  • Arthralgia (not migratory, cf acute rheumatic fever)
  • Abdo pain, diffuse, colicky, often severe – possible intussusception, melaena
  • Proteinuria (30+ mmol/mg albumin:creatinine ratio), 2+ red cells on dip or 5+ on microscopy (or casts) indicating glomerulonephritis, usually asymptomatic cf streptococcal, but a few develop diffuse proliferative lesions with irreversible renal damage.
  • Scrotal rash/bruising common, rarely torsion
  • Rarely encephalitis, seizures, pulmonary haemorrhage

Pathology

Leukocytoclastic vasculitis with glomerular mesangial IgA deposits.  Biopsy of patients with IgA nephropathy identical, and indeed both groups have defective IgA1 glycosylation, which may explain why they may aggregate and precipitate IgA in small vessel walls as well as in the glomerular mesangium.

Complications

Complications and relapse associated with age esp over 6yr. 50% relapse, usually within 6 weeks but can be up to a year later; 50% of those will relapse more than once. Treat with NSAIDs (unless renal involvement!) for joint pain, analgesics for abdo pain. Small study from Turkey found that Ranitidine reduced symptoms.

Steroids (prednisolone 1-2 mg/kg/day for 1-2 weeks) are suggested (grade 2 recommendation) within 3 days of onset of severe abdominal pain (defined as pain requiring hospital admission) or acute GI bleeding – after exclusion of intussusception, of course.

Steroids are also suggested for orchitis, after excluding torsion.

Reviewing 101 children with abdo involvement those who did not receive steroids had an average of 5 days of abdominal pain, whereas all those treated recovered within 24 to 48 hours of starting steroids (letter, J Pediatr Gastroenterol Nutr. 31(3):323-4, 2000).

Abdominal pain is a predictor of renal involvement, so maybe that’s the best reason for giving steroids… (Kidney Int 1998; 53:1755-9).

Renal disease

20 to 90% risk of renal disease, but generally mild (mostly just mild proteinuria and/or haematuria)! Normal urinalysis at day 7 has 97% negative predictive value for chronic renal disease [PLoS One 2012;7:e29512].

About 56% of those children with renal disease develop signs and symptoms of renal disease a week or more after presentation, although generally in first month.  Can be up to 6 months later.  Incidence of renal failure in HSP nephritis is just 2 to 5%.  Risk factors are severe abdominal pain (OR=2.1), age >8yrs (OR=2.7), and relapsed HSP (OR=3).[Arch Dis Child. 2010 Nov;95(11):877-82. doi: 10.1136/adc.2009.182394]

A normal urinalysisNB Children who appear to recover may have significant renal disease many years later. (Lancet. 339:280282, 1992).

If more than 50% crescents on biopsy, then poor prognosis.  Only 1% get that far.

Archimedes in 2012 found 3 RCTs of steroids, treatment courses 2-4 weeks, seemed to shorten duration of abdominal pain, with most obvious effect when used early.

Dudley trial of early steroids (day 7) failed to find any benefit at 12 months (n=352).  Quite a high proportion of drop outs unfortunately, but prob not enough to influence results.  Doesn’t answer question of what to do if severe disease at onset eg nephrotic range.  [Arch Dis Child. 2013 Oct;98(10):756-63.]

Non-randomized prospective clinical trial of 223 kids showed that steroids were effective in reducing the severity of abdominal and joint pain and in treating renal disease – steroids did not prevent the development of nephritis [Archives of disease in childhood. 2010;95:877–82, doi: 10.1136/adc.2009.182394 ].  Previous systematic review suggested that steroid treatment at diagnosis did not reduce the median time to resolution of abdominal pain but did significantly reduce the mean resolution time, and increased the odds of resolution within 24 hours.

There is no proven benefit of corticosteroids in the treatment of established HSP nephritis (2009 Zaffanello systematic review, evidence is poor), but used anyway.

The major risks of corticosteroid treatment in children with HSP are masking an acute abdomen or intussuception, and GI bleeding.

Follow up

UK Kidney association guideline 2022 – for uncomplicated presentation, do frequent dipstick checks, for example weekly for first 4-6 weeks then monthly. BP check at presentation and then if evidence of nephritis. No need for parents to check at home otherwise. 6 months minimum (audit criteria, rather than recommendation).

If hypertensive or urinalysis pos, then do proper urine protein:creatinine ratio, U&Es, MC&S. Isolated haematuria is benign. As soon as urinalysis becomes normal, child can have routine follow up.

Scottish guideline was that persisting proteinuria of + or more needs more frequent follow up eg 2 weekly, 2 monthly then 3 monthly with the second line investigations.

Refer urgently for confirmed hypertension, or nephrotic range proteinuria (P:CR over 200mg/mmol).

Refer for biopsy if persisting severe proteinuria (UP: UC >250 mg/mmol for up to 4
weeks), persisting moderate proteinuria (UP: UC 100–250 mg/mmol for 3 months),
AKI stage 1 or greater (creatinine >1.5 × previous baseline or >1.5 × upper limit of normal for age). Treatment depends on histology and severity of clinical features.

ACE inhibitor is suggested (grade 2 recommendation) for persisting mild/moderate proteinuria.

A systematic review found no risk of long-term renal impairment in children with Henoch-Schonlein purpura with normal or minimal urinary findings without nephritic or nephrotic syndrome or renal failure (Arch Dis Child 2005;90:916-20). If urine analysis is normal at presentation, then test for 6 months after the last symptoms. If there is renal disease at presentation, then the risk for progression seems to be more associated with rising proteinuria during follow-up rather than presentation features. (Am J Kidney Dis 2006;47:993-1003)

Vasculitis

General paediatrics, Immunology

Inflammation of blood vessels, clinical manifestation depends on which part of the body (often widespread) and what size vessel affected.

Classic presentations are:

  • rash esp purpuric, pernio (swelling of subcutaneous tissue),
  • ischaemia eg infarction (brain, gut, digits),
  • nephritis,
  • asthma.

The Chapel Hill system provides definitions for 10 different forms of adult vasculitis but is of debatable utility.  EULAR consensus criteria look pretty good [Annals of the Rheumatic Diseases. 65(7):936-41, 2006. PMID 16322081].

Differential: hyperlipidaemia esp severe familial, coagulopathy, fibromuscular dysplasia (familial).

Primary vasculitis

Classified by size of vessel affected (although a degree of overlap often exists):

  • Large vessel ie aorta- Takayasu. May be preceding inflammatory-type illness. ?headache/dizziness, ?inflamm eg Raynauds, episcleritis etc.  Claudication, absent pulses, subclavian bruit.
  • Medium vessel – Kawasaki disease, Wegener’s (C-ANCA pos, nasal/oral lesions, pulmonary lesions, GN, granulomata), Polyarteritis Nodosa (PAN: livedo, neuropathy, aneurysms), Churg Strauss (ANCA pos, asthma, eosiniophilia, neuropathy)
  • Small vessel vasculitis – Henoch Schonlein Purpura (HSP) is the classic one, but also cryoglobulinaemia (?hyperviscosity, assoc with malignancy and chronic viral infection)

Secondary vasculitis

eg SLE, mixed CT, infective esp streptococcus.

Investigations

Characterized by one or more anti-neutrophil cytoplasm auto-antibodies.  These are screened for by immunofluorescence (IF) that can reveal specific patterns of staining, viz pANCA (peripheral staining), cANCA (cytosol staining).  cANCA is predominantly due to Peroxidase 3 antibodies, and is seen in Granulomatosis with polyangiitis (previously Wegener’s granulomatosis, so should be Wanca?!), pANCA is mainly due to Myeloperoxidase antibodies and bacterial permeability increasing factor (BPI), and is seen in 50% of microscopic polyangiitis.

These patterns and antibodies are also associated with rheumatoid arthritis, CF, IBD, drug induced vasculitis, Churg Strauss syndrome, autoimmune liver disease etc.

But in children these are not very sensitive and in any case no evidence that distinction influences treatment or prognosis. The type of ANCA seems to be related to the population rather than the disease! Probably has direct toxic effect.

Imaging is the second modality of investigation, esp MR angiography.

Untreated, these diseases have 90% 2 yr mortality…