Fever of unknown origin in children

Overview

Most fevers in children are short and their cause is obvious. A small group of children have fever that goes on for weeks with no explanation even after a careful assessment. This is fever (or pyrexia) of unknown origin (FUO or PUO). The cause is usually a common disease presenting in an unusual way, not a rare one. The exam tests the definition, the main groups of causes, the order of investigation and the clues that point to each diagnosis.

Fever patterns: three different problems

Nelson separates three situations that are often confused:

Recurrent or periodic fevers (repeated separate episodes with well periods between) are different again: they usually represent a series of acute illnesses or a periodic fever syndrome, not one prolonged fever.

Definition and paediatric criteria

• Temperature above 38°C (100.4°F).
• Lasting more than 14 days.
• No obvious cause despite a complete history, full physical examination and routine screening laboratory tests, or after 1 week of hospital evaluation.

Normal core temperature is kept within a narrow band between about 37°C and 38°C.

Causes

Nelson's broad picture:

• Infections: the commonest group.
• Inflammatory (connective tissue) diseases: about 20%.
• Malignancy: about 10% (less common than in adults).
• No diagnosis: about 15%. In many of these the fever settles on its own without sequelae, though a few later declare a rheumatic disease.

Infections

Nelson lists the infections that most often cause PUO in children with a known or newly found immune deficiency: viral hepatitis, EBV, CMV, Bartonella, ehrlichiosis, Salmonella and TB.

Inflammatory diseases

• Systemic-onset juvenile idiopathic arthritis (Still disease).
• Systemic lupus erythematosus, juvenile dermatomyositis.
• Kawasaki disease, polyarteritis nodosa, Behçet syndrome.
• Inflammatory bowel disease (especially Crohn disease).
• Rheumatic fever, sarcoidosis, serum sickness.
• Drug fever.

Malignancy

Leukaemia, lymphoma (including Hodgkin disease), neuroblastoma, Wilms tumour, Ewing sarcoma, hepatoma, atrial myxoma.

Miscellaneous

• Factitious fever and Munchausen syndrome by proxy.
• Diabetes insipidus (central and nephrogenic) and anhidrotic ectodermal dysplasia (cannot sweat), familial dysautonomia, hypothalamic (central) fever.
• Thyrotoxicosis, Addison disease, pancreatitis, poisoning.
• Periodic fever syndromes and cyclic neutropenia.

Clinical assessment

History

Nelson's checklist of points to ask:

• How the fever affects activity and health; weight loss.
• Drugs and any immunosuppressive treatment (drug fever).
• Past unusual, severe or recurrent infections (immune deficiency).
• Immunisation status.
• Raw or unprocessed foods, unpasteurised milk (brucellosis).
• Pica and contact with soil or untreated water (Toxocara, other parasites).
• Animal contact, ticks and mosquito exposure, travel.
• Blood transfusion, recent surgery or dental work, tattoos or piercing, and sexual activity in adolescents.
• Chemicals at home or from hobbies; ethnic background (inherited periodic fevers).

Examination

Examine fully and repeat the examination regularly, because new signs appear with time. Look especially for:

• Lymph nodes, liver and spleen.
• Heart murmur (endocarditis), joints and muscles (JIA, dermatomyositis).
• Rash (JIA, SLE, Kawasaki), conjunctivae, mouth and teeth.
• Sinus, mastoid, bone and spine tenderness (osteomyelitis, discitis), abdominal or rectal tenderness (abscess).
• Signs of weight loss and pallor (malignancy, TB, IBD).

Investigations

Investigation is stepwise: simple screening first, then tests guided by any abnormality.

Screening tests (first line)

In Pakistan, add a malaria blood film or rapid test and consider typhoid culture early, as guided by the clinical picture.

Second-line tests (guided by the first results)

• TB testing: tuberculin (Mantoux) test or an interferon-gamma release assay.
• Throat swab and stool culture.
• HIV antibody, EBV antibody profile, Bartonella antibody; other serology such as brucella when exposure fits.
• Lumbar puncture for CSF analysis and culture.
• Imaging: ultrasound, CT or MRI of chest, abdomen and head; radionuclide scans.
• Bone marrow biopsy for cytology and culture (leukaemia, disseminated TB, other infections).

Interpreting the results

Management and specialist referral

Nelson's approach (Figure 96-2):

1. Detailed history and examination.
2. Unstable child or organ- or life-threatening signs: admit, take the appropriate tests and start treatment immediately.
3. Stable child with a clear diagnosis: confirm with the relevant test and treat.
4. Stable child, no diagnosis: screening tests, then reassess; if still unclear, further tests (special cultures, PCR, serology, biopsy, imaging).
5. Still no diagnosis: refer.

Points of practice:

• Prolonged observation and repeated evaluation are central; many diagnoses appear only with time.
• Avoid blind antibiotics or steroids in a stable child, because they can hide the diagnosis (partly treated endocarditis or osteomyelitis, masked leukaemia) without curing it.
• Specialist referral: Nelson suggests involving infectious disease, immunology, rheumatology or oncology specialists, depending on the leads.
• Treat the cause once found; give antipyretics for comfort and keep nutrition and hydration up meanwhile.

Prognosis

When no cause is found, the fever often resolves without lasting harm, but follow-up is needed because a rheumatic disease may declare itself later.

Fever without a focus in young children

This is not PUO, but it is examined alongside it.

Infants under 3 months

• Higher risk of serious bacterial infection; often only fever and poor feeding.
• Organisms: group B streptococcus, E. coli, Listeria in neonates; pneumococcus, Haemophilus influenzae, non-typhoidal Salmonella and meningococcus at 1-3 months.
• All febrile infants under 4 weeks, and ill-looking infants under 3 months, are admitted: blood, urine and CSF cultures, then IV antibiotics (typically ampicillin plus cefotaxime or gentamicin); add acyclovir if neonatal herpes simplex is possible.
• Nelson's low-risk infant: older than 1 month, well-appearing, no focus, no prematurity or previous antibiotics, white count 5,000-15,000/µL, and fewer than 10 white cells per high-power field in urine. Such infants can be managed as outpatients with close follow-up.

Children 3 months to 3 years

• Most have self-limiting viral illness; a few have occult bacteraemia or a UTI.
• UTI is the commonest serious bacterial infection identified in this age group, so check urinalysis and urine culture.
• Risk of occult bacteraemia rises with temperature of 39°C or more and white count of 15,000/mm³ or more; in well-appearing children vaccinated against pneumococcus and Hib it is about 0.2%.
• Close follow-up (re-check within 24 hours and over at least 72 hours) is essential whatever the treatment.
• Sickle cell disease: impaired splenic function puts these children at high risk of bacteraemia, so fever needs cultures and empirical antibiotics.

Quick revision

• PUO in a child: fever over 38°C for more than 14 days, cause unknown after full assessment, or after 1 week in hospital.
• Infections first; inflammatory about 20%; malignancy about 10%; undiagnosed about 15%.
• Local leaders: typhoid, TB, malaria, brucellosis, UTI, liver abscess, endocarditis.
• Confirm the fever; think of factitious fever.
• Screening: CBC, ESR, CRP, LFTs, urine and blood cultures, chest X-ray, ANA, RF, C3/C4.
• Then targeted tests: TB tests, serology, imaging, LP, bone marrow.
• Avoid blind antibiotics or steroids; observe and re-examine.
• Refer to infectious disease, immunology, rheumatology or oncology when unexplained.

Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).

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