Category Archives: Immunology

Muckle-Wells Syndrome

General paediatrics, Genetics, Immunology

A Cryopyrin disorder, found in Northern Europeans. Cryopyrin triggers an IL-1 dominated inflammatory response, and is coded for by the Cold-Induced Autoinflammatory Syndrome 1 (CIAS1) gene, also known as the NLRP3, NALP3 or PYPAF1 gene.

Attacks of periodic fever are very brief eg 1-2 days – apart from fever, an urticarial rash is sometimes seen, limb pain/arthralgia occurs. Abdominal pain and arthritis occur rarely. Sensorineural hearing loss is characteristic.

Amyloidosis affects 25%, which is high cf other periodic syndromes.

Diagnosis is by genetics.

Steroids are often used but benefit is inconsistent; interleukin 1 (IL-1) receptor antagonist Anakinra shows promise.

Familial cold autoinflammatory syndrome (FCAS) is a similar condition, also related to Cryopyrins. Cold induced obviously, but without the deafness, and amyloidosis is rare.

NOMID/CINCA are also related – the names say it all: Neonatal onset multisystem inflammatory disorder, and chronic infantile neurological cutaneous and articular syndrome. Papilloedema and uveitis potentially leading to blindness occur; there is epiphyseal bone formation; hepatosplenomegaly; and a chronic meningitis with deafness. There is no known treatment, sadly.



Hyper IgD Syndrome (HIDS)

General paediatrics, Immunology

Mostly Dutch and French. Not to be confused with Hyper IgE syndrome or Hyper IgM syndrome. Big database in Nijmegen. A genetic syndrome (autosomal recessive, explained by MVK (mevalonate kinase) gene mutations on chromosome 12p – see Omim) with recurrent febrile attacks starting under 1yr of age.

Attacks last 3-7 days, so may or may not be shorter than TRAPS, occur every 4-8 weeks. Features are:

  • Abdo pain, vomiting and diarrhoea (cf constipation of TRAPS)
  • Headache, arthralgia
  • Swollen cervical lymph nodes – v common, cf TRAPS
  • Splenomegaly
  • Non-destructive arthritis

Diagnosis is by finding of high IgD (>100U/ml); most also have high IgA (with or without raised IgG and IgM), which is an important clue.

Increased Mevalonic acid in urine during fever.

Febrile attacks in response to immunizations often reported, so may be another clue.

Attacks tend to diminish with age without completely disappearing; amyloidosis seems to occur only rarely (cf TRAPS). Simvastatin is supposed to help!



Familial Hibernian fever/TRAPS

General paediatrics, Immunology

First described in a family of Irish descent, hence “Hibernian”, now called TRAPS (TNF receptor assoc periodic syndrome), and now described in a wide range of different ethnicities.

Various mutations of TNF-Receptor Super Family 1A (TNFSF1A) seen, on chromosome 12p (same as HIDS but different gene). These mutations are dominant and penetrate poorly, with only a small proportion developing disease.

Onset is typically around 3yrs of age but varies widely. Periodicity also varies widely: typically every 5-6 weeks. Fever for 3 days heralds onset of other symptoms, which then last for usually 5 days or more (cf Familial Mediterranean Fever):

  • centrifugal migratory erythematous rash, often starting as a patch overlying an area of myalgia, but lots of variation
  • Myalgia – quite striking cf HIDS, uniquely can involve face and neck. CK etc are normal, so due to fasciitis not myositis.
  • Arthralgia – but arthritis uncommon, and non-destructive.
  • Abdo pain is extremely common, often with constipation but may progress to bowel obstruction. Many patients have a history of bowel surgery.
  • Eye involvement is characteristic – conjunctivitis, periorbital oedema; uveitis has been described rarely. cf Behcet’s
  • Pleuritis can occur, but chest pain is more usually musculoskeletal.
  • Lymphadenopathy is rarely very prominent, cf HIDS.

About 14% develop amyloidosis.

Diagnosis is mainly clinical. Must have at least 6/12 history of recurrent inflammatory symptoms, with at least one of the above features, episodes must last at least 5/7 on average (even if variable), with response to steroids but not colchicine. Other affected family members will obviously increase your suspicion. Ethnic group does not seem to have any bearing.

Steroids reduce severity but not frequency of attacks. NSAIDS help fever. Etanercept appears to prevent; colchicine does not (hence one of the diagnostic criteria above!). 

[Medicine 2002;81(5):349-68 PMID 12352631]



Familial Mediterranean Fever

General paediatrics, Immunology, Rheumatology

Short attacks of fever, usually lasting 1-3 days, recurring at varying intervals (periodic), cf Behcet’s.

Most children develop severe abdominal pain with the episodes, due to sterile peritonitis.

Pleuritis, leading to chest pain, arthritis, myalgia and skin rashes may also occur.

Most cases are from Arabic Turkish, Armenian or Jewish background. Inheritance is autosomal recessive. The gene has been cloned and four mutations have been identified.

Colchicine is the treatment of choice. Some patients may develop amyloidosis; certain mutations are at higher risk.



Behcet’s syndrome

General paediatrics, Genetics, Immunology

Recurrent fever and aphthous stomatitis, mostly. However, there is no regular periodicity of the symptoms, and episodes of fever may last for weeks.

Traditionally associated with Mediterranean or Eurasia but in UK mostly white Caucasian.

Other features –

  • arthritis,
  • genital ulcers,
  • iridocyclitis and optic neuritis, even blindness
  • skin rashes (classically erythema nodosum or pustulosis),
  • disabling vascular (thrombosis, superficial phlebitis) and central nervous system complications may occur.

BPSU study found 1 case every 2 weeks in the UK. Median age of onset was 6yrs – but diagnosis 11yrs!

Colchicine as regular preventive treatment, else immunosuppressive treatment. Topical steroids or short courses oral steroids.

PFAPA

General paediatrics, Immunology, Infectious disease

=periodic fever, aphthous stomatitis, pharyngitis, adenitis.

Fever every 4-6 weeks (periodic). Neutrophil count normal, cf cyclical neutropenia.

Besides mouth ulcers, sore throat and cervical lymphadenopathy, headache, musty smell (!), abdo pain.

Affected children continue to grow normally, are well between attacks, and do not suffer long-term sequelae.

Treatment with steroids or with cimetidine has been effective, and some children have had no further attacks following tonsillectomy (which suggests some relationship with strep infection but not clear).

Cyclical neutropenia

General paediatrics, Haem/Oncology, Immunology

=elastase defect.

Regular pattern of fever (periodic), approximately three-weekly, perhaps associated with malaise, periodontitis, aphthous ulceration, impetigo, sore throat and enlarged lymph glands.

But by the time the child presents, the neutrophil count may have returned to normal (although unlikely to be high).

Check FBC twice weekly for 4-6 weeks to demonstrate the fluctuation of the neutrophil (and monocyte) count.

Important not to miss, as children can develop severe bacterial sepsis while neutropaenic (mortality rate of up to 10%).

Management

Need antimicrobial prophylaxis, and possibly GCSF.

Differential is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis)



Periodic fever

General paediatrics, Immunology, Infectious disease
Infectious causes
Mycobacteria (TB and non-tuberculous disease)
Borrelia
Leptospira
Streptobacillus moniliformis (rat bite fever)
Hepatitis B
Orbivirus
Rickettsea (typhus)
Entamoeba histolytica
Others
Cyclical neutropoenia
PFAPA
Behcet’s
Hyper IgD (HIDS)
Familial Mediterranean fever
Familial Hibernian fever/TRAPS
Cryopyrin disorder

Periodic fevers are defined as uniform periods of fever that recur regularly in individuals who are healthy between attacks. Parents may organize life eg holidays around expected attacks and don’t have any concerns otherwise cf child with recurrent respiratory and gastrointestinal infections after starting nursery who “always has something”.

Recurrent bacterial infections esp recurrent/chronic pneumonia or otitis media may indicate a humoral immune defect. Similarly, recurrent documented viral or fungal infections may indicate a cell mediated immune defect.

Allergen families

Allergy, General paediatrics, Immunology

Hundreds of different allergens have been identified, and can be classified by similarities in structure/genetics, usually based on the plants being related to each other in evolutionary terms.

This is useful because cross reactivity is more common, the more closely different proteins are related. Not all are allergenic however, and not all cross react.

You can also predict how heat stable these proteins are by how cross linked their structure is. Linear proteins are more easily disrupted by heat, so the allergy is likely to only be an issue with raw (or frozen from raw).

Most allergens belong to one of a small number of groups:

  • PR-10 eg Bet v 1, Ara h 8, Cor a 1, Pru p 1, Mal d 1. Heat labile, homologous. Most pollen food syndrome cases (birch pollen).
  • Profilin eg Bet v 2, Cor a 2. About 20% of pollen food syndrome cases. More common in Southern Europe – birch and oak too, but also olive tree, London plane, grasses (eg Phl p12), ragweed. More common in high grass pollen intensity areas? Citrus, tomato, banana, melon/watermelon (but different from latex-fruit syndrome). Can be associated with severe food reactions (not citrus so much but the others).
  • Prolamin – includes nonspecific lipid transfer proteins (nsLTP) which are heat stable but very cross reactive, and are found in fruit, vegetables, nuts, legumes, seeds and cereals. Best known is Pru p 3, which is a good surrogate marker for any nsLTP sensitisation, even if peach (prunus persica) isn’t a known issue. Ara h 9, Cor a 8, Jug r3, Mal d 3. Mugwort related pollen food syndrome is usually due to an LTP (Art v 4 with Api g 4 of celery and Dau c 4 of carrot, else Foe v 5 (fennel), Sin a 3/4 of mustard). Severe reactions possible.
  • Cupin – includes legumins. Heat stable. Ara h 1 and 3, lentil, cor a 9/11 (hazelnut), some soya.
  • Thaumatin – named after W African shrub! Various fruit including apple, kiwi, plus cedar pollen.
  • 2S albumin eg Ara h 6.

Glasgow lab offers only hz, peanut, peach/cherry, egg (Gal d 1), alpha galactose and bee/wasp. Dundee offers those plus milk and cashew.

Private testing available for Bos d 8 (milk casein) and soya.

Atopy

General paediatrics, Immunology

Funny old word – means “without place” in Greek, which refers to the fact people didn’t know what was going on with these kids – not the mechanism, not a particular infection, not a specific organ or system.

Some clues from genetic mutations – JAK1 mutations are a cause of severe atopy and eosinophilia. Involved in IL-4, IL-13, and IFN signaling. Long-term ruxolitinib (kinase inhibitor) treatment of 2 children carrying the JAK1GOF (p.A634D) variant improved their growth, eosinophilia, and clinical features of allergic inflammation.

The idea of the immune system being about defence is wrong! Tolerance is everywhere! B and T regulatory cells keep everything under control.

Microbiome in atopic conditions different, and differences can precede disease.

Neonatal gut microbiome predicts sensitisation (3 groups). Main differences are bifidobacteria and enterobacteria. Differences are related to maternal diet, delivery method, feeding method, antibiotic exposure etc.  Cumulative effect.  Still apparent at age 3.

Breast milk contains 1/3 oligosaccharides that are not digestible by baby!  Designed for microbiome!? Some genetic variations. Oligosaccharide composition associated with later sensitization.

Short chain fatty acids eg butyrate associated with sensitization – yogurt! Component of soluble fibre! Affect T reg cells.

Morganella morgani produces histamine!  Higher levels in asthma, esp higher risk.

[Liam O’Mahony – Cork, prev Davos]

Karelia study – biodiverse environments eg forest and agricultural had greater diversity of skin microbiota cf urban, shore.  Inversely related to atopy, and IL10 expression. [Finland now has national programme for allergy prevention]