Category Archives: Immunology

Pyrexia of Unknown Origin

A technical term, not just a fever without obvious source! Essentially presence of confirmed fever for 8 days or more in a child in whom a careful thorough history and physical examination, and preliminary laboratory data fail to reveal a probable cause.

Long list of possible causes, long lists of possible tests – do thorough history and repeated examinations, then follow the clues!

In kids, infection is the commonest cause. But can be connective tissue disorder, or malignancy.

Beware factitious fever – admission sensible.

If possible, stop all drugs. Antipyretics may obscure the pattern of fever, and can occasionally be its cause (drug fever is one cause).

Unless the child is critically ill, try not to give antibiotics. If the diagnosis remains obscure, go back and take the history again, examine the child (fully) again, send the specimens again!

Special points in history/examination

  • Travel – malaria can present 6-12 months later. Typhoid.
  • Ethnicity – tuberculosis
  • Outdoor activities – rats/ticks as vectors of infectious diseases
  • Animal contact – cows/sheep (brucellosis), cats (cat scratch)
  • Mouth ulcers (IBD, Behcets, PFAPA)
  • Periodicity – see Periodic fever
  • Sinus tenderness, nasal congestion (sinusitis)
  • Bone/spine tenderness – discitis, vertebral osteomyelitis


  • 3 sets of blood cultures, different sites, different times (at least a few hours apart), off antibiotics – standard for endocarditis
  • ASOT
  • EBV, CMV
  • LDH, CK
  • ANA/RF
  • Urine/stool culture
  • Swab everything!

Allergy testing

Gold standard is double blind challenge, but who has time for that?

Mostly based on history – combination of characteristic features without other, more likely, explanation.

NICE has list of type 1 vs non type 1 allergy signs/symptoms – some overlap, eg vomiting, diarrhoea, itch.

EAACI guidance 2023 says where type 1 allergy suspected (signs/symptoms but also timing and consistency of reaction):

  • Do skin prick testing and/or specific IgE testing as first line
  • For peanut, hazelnut or cashew, if in doubt do component tests Ara h 2, Cor a 14, Ana o 3 respectively as well (if available) – otherwise do skin prick or IgE if not done already.
  • Where peanut or sesame allergy still in doubt, do basophil activation test (BAT – if available)
  • “Reassessment of food allergic children, at regular intervals, depending on age, food and patient’s history, is suggested for possible development of spontaneous tolerance”

Ara h 2 (cut off 0.44) has 82% sensitivity and 92% specificity cf 84 and 86% for SPT of 4mm. Cor a 14 (cut off 0.64%) has 73 and 95%, Ana o 3 (cut off 0.4) 96 and 94%.

Common hidden allergens (!): celery, mustard, cochineal, lupin, soy, fenugreek, other legumes such as pea/bean/lentil protein, insects/mealworm, pink peppercorns).

Allergies and School/Nursery

First do no harm – parents tend to overestimate risk of anaphylaxis, whereas there are clear consequences to restricting the child’s ability to sit with other children at snack/meal times, or restricting the food choices of other children.

Probably better to increase allergy awareness (which varies widely) than rely on classroom or school-wide bans [Dave Stukus editorial]

George Raptis has shown how allergy training can improve allergy awareness, not just confidence in managing an allergic emergency.

Onion and garlic allergy

Alliums, as are leeks, shallots and chives. Part of same bigger family as asparagus but probably not co-sensitivity.

The main issue with onion is the chemicals released from cut surfaces, which can trigger eye/nose reactions and potentially asthma. But there’s actually some evidence that onion has an anti-allergy action.

With garlic, there is a well recognised contact dermatitis relating to chopping it.

Otherwise, allergy is very rare. Potentially part of celery-spice-mugwort syndrome.

As with that syndrome, the problem for the allergic person is that not only is it not one of the 14 UK recognised allergens for food labelling and restaurants, but it can be included under “spices” if less than 2% of the overall product, without further detail.

Food allergy

Different from intolerance and sensitivity, which are not immune mediated problems. Sometimes hard to tell the difference.

2 types of food allergy, you can have both at the same time – type 1 (IgE mediated), and non-type 1 (non-IgE mediated – possibly type 4 hypersensitivity).

Most commonly (in Scotland – but varies across UK, especially with different ethnic groups), and varies widely across the world):

  • Milk
  • Egg
  • Peanut
  • Tree nuts
  • Legumes/Pulses
  • Sesame
  • Wheat
  • Crustaceans/molluscs
  • Various fruits

Hospital admissions for food allergy in the UK have been increasing for some time. If you ask people about their children’s allergies, up to 28% of infants will report allergies – real figure is probably between 1 and 4%. Lifetime and point prevalence of self-reported food allergy 20% and 13%, respectively – point prevalence of sensitization as assessed by sIgE stands at 17%, skin prick test 6%, and food challenge positivity 1%. Based on clinical history or positive food challenge, food allergies have increased from 2.6% in 2000–2012 to 3.5% in 2012–2021. Point prevalence for under 16s for self reported but physician diagnosed food allergy is 3.75%. Patterns vary across European regions but not in a consistent way. [Spolidoro and Venter 2022]

Having a child with a food allergy has a significant effect on the quality of life for the whole family. One study suggested that having a peanut allergic child had a worse effect on a family than having a child with diabetes, even though with diabetes you also have restrictions on eating and the potential for serious adverse events. A similar study found the same comparing food allergic families with families where a child had a rheumatological diagnosis. The main domains affected were social. Patient/parent feedback pretty consistent across the world however (although most studies done in Europe and English speaking countries), and across time:

  • Parents lived in fear after the first reaction, often perceiving it as traumatic, and often feeling guilt too
  • They tried to live an ordinary family life and had to learn how to be one-step ahead and understand early signs.
  • The family’s social life was also influenced.
  • Parents asked for support and information from health professionals
  • More knowledge and skills increased parents’ confidence (and by implication quality of life – Knibb 2015)

Mothers tend to report greater impact on the child’s quality of life and experience more anxiety and stress than fathers. Mothers tend to shelter the child, whereas fathers more often express a desire to expand their child’s life, and these differences are often greater where parents are separated.

The concern for the child’s safety affected eating outside the home, with birthday parties and visits to peers’ homes particularly threatening. School and nursery are a major source of concern and often led to more parental work, preparing safe lunches.

Parents often felt they had to teach themselves about allergies, due to the lack of early information provided by health care, and then ended up having to teach family, friends and educational institutions too.

Adolescence is a particularly stressful time, as parents recognize the need for the child to become more independent, at the same time that the adolescent can see the parents as excessively controlling (at least with respect to peanut allergy). Supportive friends particularly important for adolescents.

[Larsen Moen, J Ped Nursing 2019]


Initial studies did not show any relationship between moulds/damp and health, as there was major confounding with socioeconomic status, and because it is hard to quantify mould exposure (with many different mould species).

Then there is the effect of climate, and the built environment – heating, ventilation, insulation, materials etc.

More recently systemic reviews have made it clear there is a link particularly with development of asthma, particularly in older children, and where there is already a family history of atopy.

Longitudinal studies have suggested that there may be protective effects but data is limited.

Similarly there is evidence that higher exposure to moulds leads to more asthma exacerbations.

There are genetic polymorphisms that affect ability to break down the fungal protein chitin, and these have been linked to urgent medical care visits, which suggests a non-immune mechanism may be important.

Dampness is linked to mould growth but also to house dust mite, microbial volatile compounds, mycotoxins and endotoxin.

The most studied mould species are AspergillusPenicilliumAlternaria and Cladosporium.

Limited evidence that interventions to reduce mould make any difference.

[European respiratory review 2018]

Muckle-Wells Syndrome

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)

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

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]