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Thrombosis

General paediatrics, Haem/Oncology

The basic coagulation screen is PT, APTT and Fibrinogen.

  • PT – liver disease, warfarin, DIC
  • APTT – haemophilia, heparin, DIC, anticoagulant eg lupus anticoagulant
  • Fibrinogen – congenital hypofibrinogenaemia, DIC

A prolonged APTT which corrects (at least partially) on mixing with normal plasma is deficient in clotting factors. If correction is not possible, then must be an anticoagulant.

The more advanced coagulation tests are:

  • Diluted Russel Viper Venom Time (DRVVT)
  • Kaolin Clotting Time (KCT)

Basic thrombophilia screen is:

  • Protein C/S
  • Anti-thrombin III
  • Prothrombin mutations
  • Factor V Leiden mutation
  • Homocysteine

Protein C and S can be transiently low with acute thrombosis. Levels also affected by warfarin but not by LMWH.

Factor V Leiden

Most common inherited thromophilia in Europe. Co factor for factor X. Autosomal dominant so variable penetrance. Rare in East Asian and African.

Anti-Phospholipid Syndrome

Antiphospholipid antibodies are a mixed bag:

  • Lupus anticoagulant – total misnomer, as it is PRO-thrombotic and only occasionally associated with lupus! Anticoagulant only in vitro. Overall, found in 1-5% of normal population, though in low titre, usually IgM and transient. Persistent positivity is strongly associated with venous thrombosis and stroke and fetal loss.
  • Anticardiolipin is more associated with pregnancy morbidity than with thrombosis, and is less predictive than LA.
  • Anti beta2 glycoprotein 1 (beta2Gp1) antibodies are less well established as an independent risk factor but are cumulative with the other 2.

An autoimmune disorder of recurrent thrombosis and pregnancy loss! Migraine, livedo, raynauds, unexplained persistent thrombocytopenia can be clues. Not well defined in children, usually heralds SLE and is probably much the same thing.

There is no one antiphospholipid syndrome, despite the name! All have persistent antiphospholipid antibodies (of one sort or another) plus 1 or more clinical criteria:

  1. thrombosis
  2. pregnancy related morbidity:
    • unexplained IUD beyond 10/40 with normal morphology
    • preterm (<34/40) due to pre-eclampsia/placental insuff
    • 3+ unexplained consecutive miscarriages

For lab, must test positive on 2 occasions, 12+/52 apart. Testing is affected by warfarin and heparin.

Antiphospholipid syndrome occurs in isolation in more than 50%. 30% of SLE patients get it. A catastrophic clinical presentation can occur with multiorgan involvement (pulmonary haemorrhage, ARDS, cerebral/adrenal infarction, Budd-Chiari), microangiopathic thrombocytopenia, haemolysis similar to TTP/HUS/DIC (Rx anticoagulation, high dose steroids, plasma exchange, IVIG).

Acute treatment is with IV or subcut heparin, followed by warfarin (target INR 2-3). Aspirin may be added if problematic. Hydroxychloroquine should probably always be used. Avoid smoking, oestrogens, cocaine… Plasma exchange and Rituximab may be used in life-threatening cases.

The antibodies act by inducing adhesion molecules from endothelial cells, upregulating tissue factor, activating platelets and the complement cascade generally.  [Current Opinion in Hematology. 13(5):366-75, 2006]

[BMJ 2010:340;1125]

Von Willebrand disease

General paediatrics, Haem/Oncology

Presents with mucous membrane bleeding (eg epistaxis, ecchymoses, menorrhagia, and excessive bleeding with surgical or other invasive procedures esp post adenotonsillectomy). Not usually petechiae (more commonly associated with platelet function defects) but may be seen esp if aspirin/NSAID has been taken. Not usually haematomas (more characteristic of hemophilia) but may be seen if severe vWD. Menorrhagia is a frequent presentation in women.

vWD has been reported in association with hemorrhagic telangiectasia (Osler-Weber-Rendu) syndrome; so consider telangiectasias contributing eg recurrent epistaxis or gastrointestinal bleeding.

Diagnosis may be missed esp in mild vWD, because vWF levels are influenced by factors such as age, inflammation, stress, pregnancy, hormonal cycles, hypo- or hyperthyroidism, and various medications. Hence stress and inflammation due to illness (eg ruptured appendix) may reduce symptoms, whereas minor surgery in the nonstressed patient may be associated with severe bleeding! Family history should be positive, as VWD is mostly inherited in autosomal dominant fashion.

Although men and women are affected equally, women may be recognized more often because of menorrhagia and excessive bleeding with childbirth.

vWF binds platelets in plug formation. It is also a carrier for Factor VIII – without it factor VIII is lost from the circulation. Subtypes:

  • Type 1 is the commonest and the mildest – simple deficiency.
  • Type 2 is mutant vWF, so doesn’t work well. Type 2B binds platelets spontaneously leading to thrombocytopenia.
  • Type 3 is total absence, factor VIII usually low (3-5% of normal) – severe, very rare (usually autosomal recessive).

Diagnosis

Bleeding time is not particularly sensitive or specific. Prothrombin time is normal. APTT may be prolonged, depending on the impact on factor VIII. Specifc vWF antigen/activity tests (Ristocetin stimulates platelet aggregation in presence of vWF) available.

Treatment

Desmopressin (DDAVP) is available in IV form and concentrated intranasal form (not the same as used for enuresis and diabetes insipidus!).

  • IV desmopressin = 0.3 mcg/kg in 25-50 mL normal saline over 30 minutes.
  • Intranasal desmopressin = 150 mcg (one puff) for under 50 kg and 300 mcg (two puffs) for those over 50 kg.
  • Side effects are minimal and include facial flushing, headache, or mild increases in pulse rate or blood pressure that resolve when the infusion is slowed or discontinued. Rare cases of seizures and central nervous system injury that are associated with hyponatremia have been reported.
  • In type 2B desmopressin may worsen platelet count.

Several vWF concentrates are available, with different ratios of vWF to Factor VIII – used to cover surgery. Maximal increase in VWF/FVIII occurs at 30 to 60 minutes, so time the infusion as close as possible to the surgical procedure. The response time varies between individuals and tachyphylaxis (ie reduction in effect) may occur with repeated doses of desmopressin. A trial to establish effectiveness (judged by vWF:RCo (Ristocetin) level) may be helpful.

For major surgery, give concentrate every 12 to 24 hours for 2 to 3 days to achieve levels of VWF greater than 40%. In patients who have decreased baseline VWF:RCo, levels should be measured daily and extra doses concentrate should be administered if tachyphylaxis occurs. In patients in whom FVIII:C levels also are decreased, FVIII:C should be monitored and maintained at a hemostatic level as recommended for hemophilia A. In Type 2B give platelets if low count.

Antifibrinolytics eg tranexamic acid are useful esp for oral/nasal mucosal bleeding. Can even be used topically (mouthwash).

Alagille Syndrome

Cardiology, Congenital, Gastro, General paediatrics, Neonatology

Autosomal dominant condition (70% sporadic) with characteristic facies, biliary hypoplasia, vertebral and cardiac abnormalities. JAG1 gene.

Paucity of intrahepatic bile ducts so typically prolonged jaundice, but depending on how many ducts, may not be obvious in first few months. Jaundice gradually improves, but only minority clear completely. 30% progress to cirrhosis.

Posterior embryotoxon (white ring at periphery of cornea) is a clue, but seen in 10% of normal population so not specific.

Cardiac includes pulmonary stenosis, Tetralogy of Fallot.

Facies: broad forehead, triangular face, deepset eyes, long nose with bulbous tip.

Butterfly vertebrae characteristic (asymptomatic – see on chest x-ray).

Other:

  • Renal Tubular Acidosis, renal cysts
  • Growth failure
  • Pancreatic insufficiency

Fruit allergy

Allergy, General paediatrics, Immunology

A range of possibilities!

  • Isolated type 1 allergy
  • Multiple type 1 fruit allergies – usually to similar fruit but also some common co-sensitivities eg banana/melon/avocado/chestnut/latex group
  • Oral allergy syndrome (pollen food syndrome) – esp peach and related stoned fruit, cross reactivity with pollen (so hay fever), sometimes nuts too. Various patterns depending on allergen family.
  • Salicylate intolerance (so not allergy) esp cherries, raw tomato, pineapple juice
  • Histamine-releasing foods (wine famously, otherwise strawberry, papaya, kiwi and pineapple)
  • Naturally occurring serotonin (tomato again, banana) and tryptamine (tomato again, plum) cause allergy like symptoms [EAACI 2023]

Berry allergy

Some evidence of cross reactivity between raspberry and strawberry but there’s not much evidence to suggest cross reactivity with other berries.  There’s a theoretical link with blackberry, and other things in the same family (Rosaceae – massive group of fruit including apples, peach, pear, apricot, cherry).

Only one report of blueberry allergy ever!

Found one paper that said tree nuts, celery and parsley might also be related to berries, but again I think theoretical.

Pineapple allergy

Can be part of pollen food syndrome (due to profilin allergy) so mostly oral symptoms, hay fever, cross reactivity with other fruits as well as nuts.

Might be salicylates as above rather than allergy.

But can also be allergy to bromelain (similar to papain), with potential for anaphylaxis.

Sometimes associated with latex-fruit syndrome and ficus-fruit syndrome (all tropical, not latex – kiwi, papaya, avocado, banana).

Melon allergy

Can be part of banana/latex group, but also cucurbitae – watermelon, cucumber, courgette, pumpkin.

Juvenile Myoclonic Epilepsy

General paediatrics, Neurology

Common form of childhood epilepsy. cf juvenile absence epilepsy.

One or more of:

  1. Myoclonic jerks on waking and first hour of day, esp if tired
  2. Absences (typical) in about half
  3. Tonic-clonic, on waking and first hour of day, esp if tired
  • Precipitated by alcohol, arousal!
  • Mid teens, hence alcohol/arousal…
  • 3-6 Hz spike and wave seen on EEG.
  • Often photosensitive (40%), unlike Juvenile absence epilepsy.
  • Very sensitive to valproate. Else lamotrigine, levetiracetam.
  • Usually life long, despite the name.

Juvenile absence epilepsy

General paediatrics, Neurology

Quite different from childhood absence epilepsy! Less nice.

  • Rare
  • Onset 9-12 years but occasionally younger.
  • Non-remitting, despite the name
  • Longer absences eg 45 seconds, more frequent
  • Automatisms (eg eye flickering, lip smacking), may be able to continue some automatic activities during absence
  • Occasional tonic clonic seizures, myoclonic jerks despite the name! But much less commonly seen than in juvenile myoclonic epilepsy (JME).
  • Not photosensitive cf JME.
  • Treat with valproate, ethosuximide (unless tonic clonic seizures), or lamotrigine.

Fatty liver/MASLD

Gastro, General paediatrics

Not v uncommon in obese children/adults, which is logical. But non-alcoholic fatty liver disease (97% of which is Metabolic dysfunction associated steatotic liver disease (MASLD)) may progress to steatofibrosis, non-alcoholic steatohepatitis (NASH), cirrhosis, liver failure and hepatocellular carcinoma. It is now the most common cause of liver disease in adolescents and amongst the top three indications for liver transplantation in adults.

Data from 2020 in US found prevalence of 20% for obesity and MASLD among 12-17yr olds, with about 70% of obese adolescents affected by MASLD. More common in boys, particularly among Mexican American adolescents. Adolescents with MASLD had significantly higher triglyceride levels and alanine transaminase (ALT) levels, along with lower high-density lipoprotein (HDL) cholesterol. Insufficient physical activity and poor diet quality were key risk factors, not surprisingly. 

And not all cases are obese.

Alcoholic fatty liver disease is a different thing – depends on type of beverage, genetic risk factors, drinking pattern, duration of exposure etc so unpredictable. 

Particularly likely to progress when co-exists with metabolic syndrome (obesity esp high waist circumference, high blood pressure, high insulin resistance, high lipids).  Some polymorphisms also contribute higher risk of progressive disease.  So family history important too.

Some drugs can contribute, including methotrexate, steroids, valproate.

On examination, look for acanthosis nigricans (marker of insulin resistance) as well as signs of chronic liver disease. Hepatomegaly suggests an alternative diagnosis.

Investigations

Essentially to assess co-morbidity and exclude other causes:

  • Fasting serum glucose/ insulin.
  • HOMA-IR (fasting glucose x fasting insulin/ 22.5)
  • HbA1c measurement
  • Renal function tests
  • Vitamin D level
  • Assessment of liver function and screening for other causes of raised transaminases/ steatosis
    • First Line Investigations: ALT, AST, ALP, GGT, Split bilirubin, FBC, Coagulation screen, Albumin, Fasting lipid profile, Immunogloblins and complement levels, Autoimmune profile including ANCA, Anti-transglutaminase antibodies, Thyroid function tests, A1AT level and phenotype, Copper and caeruloplasmin, Plasma free fatty acids, amino acids, organic acids, uric acid, acylcarnitines, and lactate, Hepatitis A, B, C and E serology
    • Second line investigations: If raised triglyceride level consider Lysosomal acid lipase, 24-hour urine copper collection, ophthalmic examination and/ or genetic testing for Wilson’s disease. If organomegaly/ raised uric acid/ raised lactate or a history of hypoglycaemia consider genetic testing for glycogen storage disease

So pretty much as for viral or autoimmune hepatitis.

Non-invasive measures of fibrosis available in some centres.

Reasons to refer to liver unit

  • Age < 10yr
  • Evidence of alternative cause for steatosis detected through screening investigations
  • Presence of metabolic syndrome, type 2 diabetes mellitus, and/ or hyperlipidaemia
  • Increased AST/ALT ratio (>1) and/or a raised AST/ ALT (≥80IU/L)
  • Raised serum level of GGT
  • Child has panhypopituitarism
  • Raised non-invasive marker of fibrosis measurement
  • Presence of hepatomegaly/splenomegaly
  • Thrombocytopenia
  • Jaundice
  • Synthetic dysfunction (raised PT or low albumin level)

  [Caroline says only if double normal)

Patient information leaflets and guidance for NAFLD are available via the Children’s Liver Disease Foundation at https://www.childliverdisease.org

[BSPGHAN 2020 guideline]

Salicylate intolerance

Allergy, General paediatrics, Immunology

Can cause allergy like symptoms eg wheezing, itching, swelling, nasal congestion. Also headaches, abdo pain. Anaphylaxis reported.

Found in foods, medicines, beauty products.

High levels:

  • Cherries and strawberries, tomato (raw)
  • Ginger, mustard, curry powder (?) 
  • Liquorice and mint

Pineapple juice high but fruit itself not listed!?

Medium:

  • Black pepper
  • Sweetcorn
  • Fizzy drinks
  • Ketchup, Worcestershire sauce
  • Honey


Benzoates related.  A variety of other foods esp fruits but also avocado, vegetables, nuts, coffee, beer too.

Management

If suspected, exclude high salicylate foods only to begin with, and limit medium salicylate foods if possible.  4/52 minimum.  Includes topical including anything with “Natural plant extracts”. 

If improves, excluded medium too for further 2/52 to see if additional benefit. 

(draft BDA FAISG)

SIGN/BTS Asthma guidance 2016

Common, General paediatrics, Respiratory

Superceded by SIGN/BTS 2019.

For suspected asthma, where child unable to do spirometry, then watchful waiting or trial of treatment for specified time period.  Choice of treatment depends on severity and frequency of symptoms – “typically 6 weeks inhaled steroid”, “very low dose”.

Start regular preventer treatment or escalate treatment if you are getting frequent symptoms, viz:

  • three times a week or more, or
  • using your blue inhaler three times a week or more, or
  • if your asthma is waking you up once a week or more.

Start regular preventer if asthma attack in previous 2 years!

Same table for all ages now, and same steroid doses!

Step 1 – very low dose inhaled corticosteroid (ICS).  OR leukotriene receptor antagonist (LRTA) if under 5.

Step 2 – Add LRTA if under 5, else inhaled long acting Beta agonist (LABA) if 5+.

Step 3 – If no response to LABA, stop and increase ICS dose.  If some benefit from LABA continue and increase ICS dose, or consider trial of LTRA.

Step 4 – high dose therapies: increase ICS dose to medium, or add slow release theophylline.  Refer for specialist care.

ICS doses

Very low dose is 50mcg 2 puffs twice daily of beclometasone.  Low dose is double that, medium 200mcg 2 puffs twice daily.

QVAR and fluticasone are double the efficacy of beclometasone so doses are halved.  Ciclesonide is somewhere in between.

Lowest Observed Adverse Effect Level

Allergy

“Highly allergic” or “severely allergic” can mean low threshold for reacting, or severe previous reaction, or both!

Lowest observed adverse effect level is the formal term for the minimum dose at which you react! An eliciting dose (ED) can then be calculated through multiple food challenges for a stated proportion of the allergic population. For example, 1 peanut =150mg protein. ED 1 (where 1% of allergic population will react) is 1.3mg. But range of reported values – type of peanut allergy? Entry criteria? Boiled or roasted? Criteria for stopping challenge?

Higher eliciting dose predicts future tolerance, at least for milk and peanut, maybe not for egg.

Children probably more sensitive although ED 10 similar for children and adults.

Conflicting evidence on severity of reaction vs threshold.  Certainly trace amounts can cause anaphylaxis in some cases.  Higher fat content delays absorption, so the reaction (when it happens) can still be severe…

ED05 of 1.5mg for peanut seems safe [Hourihane].

Being cross allergic to other things might help predict – in French study, 3 phenotypes emerged from cluster analysis:

  • Cluster 1 have high level of rAra h 2 (mean 81), low threshold reactive doses for peanut and high proportion of asthma;
    • Cluster 2 (mostly boys), have high threshold, milder symptoms, and the lowest proportion of asthma/AR and cross-allergy to TN and/or legumes;
  • Cluster 3 have low Ara h 2, high risk of cross-allergy to TN and/or legumes, and most patients suffer from eczema.  [Matthias Cousin, Lille, PAI]

Complicated though – thresholds vary up to 10x for individuals in sequential challenges (n=14)!

On the day factors – alcohol/meds, infection.  Exercise is a factor in 15-20% of anaphylaxis episodes according to German/Austrian registries.

TRACE peanut study – 45% reduction in threshold for exercise and sleep deprivation (independent) esp at lower eliciting doses. ED1 and ED5 remain above 0.2 though.

Sleep deprivation (sleep overs!) worsened severity of reactions too, by 48% – exercise 28%, not significant. Repeated challenges also seemed to increase severity. [score for severity using Practall criteria. JACI 2022 Dua]

Lower thresholds had higher BAT and SPT – 8mm cut off had 100% sensitivity and NPV for severe reactions, and 92% specificity. Has nomogram combining all tests! SPT 6mm had 92% sensitivity, 95% specificity and 100% NPV for low threshold.  [JACI 2020, Santos study – LEAP cohort]

Particulate contamination risk seems to be a particular problem for milk in chocolate – big range of values found cf peanut.

UK and Europe look at processes as the way to assess risk of contamination with allergens. But not consistent between countries of the EU, let alone globally.

Quantitative methods would  appear to make sense – how much allergen is actually present in a given sample? But of course one sample may differ from another (“particulate contamination”).  Also difficult to establish minimum eliciting or threshold dose (consider denaturation of the allergen during processing, derived ingredients eg glucose syrup from wheat, soya lecithin, effect of food matrix, individual factors). 

Australia and NZ use lowest observable adverse event level (LOAEL) already – warnings required within 10x concentration of LOAEL (“VITAL” threshold, as in toxicology).  Studies from Europe and US have found most advisory warnings used for ingredients below the VITAL threshold.

But then it depends on how much you eat, as well as presence of other co-factors that are known to contribute to risk of anaphylaxis.

[BMJ 2011;343:830][Allergy 2021, Paul Turner]