When to go on a zebra hunt
A four-year-old boy presents in the paediatric ED with a week-long history of fever. His parents report that this is the first time their child has experienced such a prolonged period of fever.
What are your first steps?
What counts as prolonged fever?
Daily fever of >38°C lasting longer than five days (NICE guideline fever in under 5s)
Hang on, isn’t that common?
Yes, it is, and common things are common. First steps include a thorough medical history, physical examination and basic investigations (urine MCS, respiratory swabs, CXR). If, despite all these, you can’t find the culprit, it’s time to hunt some zebras.
What to ask in the history:
- Fever pattern
- Localising / systemic symptoms
- Recent surgery/metal work / prosthetic valves
- Infectious contacts /recent (and any previous to high-risk area) travel / outdoor activities
- Animal contacts
- Vaccination status
- Sexual activity (in adolescents)
The patient is fully vaccinated with no recent travel or animal contacts. Parents report he had been lethargic and miserable with an intermittent high spiking fever above 40°C.
On examination, you note widespread lymphadenopathy and hepatosplenomegaly. He is pale with some petechiae.
You take bloods (including a correct sample for blood culture), start on a broad-spectrum antibiotic and admit to the ward.
So, what are my ‘zebra’ differentials?
The three leading causes of prolonged fever are infection, autoimmune disorders and malignancy.
Which infections should I be considering?
Viral*
| Cardinal Features | What not to forget | |
| Adenovirus | Fever, pharyngitis, coryza, respiratory involvement (can also be GI involvement and bilateral conjunctivitis) | |
| EBV | Fever, pharyngitis and lymphadenopathy. Most common in adolescents. | Remember to warn to avoid contact sports for three weeks due to risk of splenic rupture |
| CMV | Pharyngitis, splenomegaly and deranged LFT’s (may take several months to normalise) | |
| Measles | Prodromal ‘three Cs’ (cough, coryza, conjunctivitis). Koplik’s spots (white spots in the mouth) and an erythematous maculopapular rash, classically starting behind ears. | Have a high index of suspicion in unvaccinated individuals. Measles is a notifiable disease. Notifiable diseases and how to report them – GOV.UK |
*consider HIV if risk factors are present
Bacterial
| Cardinal Features | What not to forget | |
| Cat scratch disease (Bartonella henselae) | Starts with a papulopustular lesion at inoculation site progressing to regional lymphadenopathy and systemic features. Conservative management (consider azithromycin in severe cases). | Ask about pets and animal exposure |
| TB (Mycobacterium tuberculosis) | A multisystem disease with a wide range of presentations Key features of primary (pulmonary) TB are cough, night sweats, weight loss and haemoptysis. | TB should be considered particularly in patients who have visited/have been in prolonged contact with those from high-prevalence areas. Diagnostic testing for TB can be challenging, as the organism is slow-growing and hard to culture |
When should I consider an autoimmune cause of prolonged fever?
When there is a child with a high-spiking fever who remains unwell or deteriorates despite broad-spectrum antibiotics.
You are called to review the patient later that evening.
Their bloods show pancytopenia, an elevated LDH and raised uric acid. The CRP is mildly elevated, and the culture at 24 hours is negative.
What autoimmune causes should I be considering?
- Kawasaki disease – is characterised by medium artery inflammation with multiorgan involvement. Predominantly affects the under 5’s. Cardinal features are fever > 5 days plus >4 of: erythema/cracking of lips, bilateral non-purulent conjunctivitis, rash, erythema/peeling of hands and feet, cervical lymphadenopathy > 15 mm. Children are classically extremely miserable. IVIG and aspirin treatment are required to prevent the development of coronary artery aneurysms.
- PIMS-TS (paediatric inflammatory multisystem syndrome temporally associated with COVID-19) – this condition is becoming rarer. However, it should still be considered in the older child with a Kawasaki / toxic shock-like presentation and a history of COVID-19. Patients are likely to be significantly hypotensive (with particularly low diastolic pressures) and require PICU admission for vasopressor support, IVIG, methylprednisolone and potentially biological therapies.
- SoJIA (systemic onset juvenile idiopathic arthritis) presents with oscillating fever, erythematous migratory rash and arthritis. Patients are less unwell than those with HLH and Kawasaki disease.
- Haemophagocytic lymphohistocytosis (HLH) is a hyperinflammatory state presenting with unexplained fevers, hepatosplenomegaly and cytopenias with involvement of multiple organ systems. HLH is life-threatening, and patients are likely to require PICU admission. Treatment is aimed at treating the triggering factor and dampening the inflammatory response.
Results are negative for common autoimmune diseases, and a cardiovascular examination, including echo, does not reveal aneurysms.
The blood film shows lymphoid precursors.
The primary paeds team asks for consultation from the heme/onc team.
So, if I’ve ruled out infectious and autoimmune causes, what malignant causes should I consider?
- Leukaemia – ALL (acute lymphoblastic leukaemia) and AML both present with infiltrative features (lymphadenopathy & hepatosplenomegaly), haemorrhagic features, fever, recurrent infections, and systemic features. ALL tends to feature bone / joint pain (always consider as a differential in the limping child), whereas AML can present with mediastinal/abdominal masses. Send an FBC, film (to look for blasts), X-ray the chest and US the abdomen. Definitive diagnosis is by bone marrow biopsy. Treat for intercurrent infection (use broad-spectrum antibiotics (e.g., piperacillin/tazobactam) if neutropenic and refer to local oncology services.
- Hodgkin’s lymphoma – suspect in the patient presenting with painless lymphadenopathy (including features of mediastinal mass), fever, night sweats and weight loss. Investigate AML/ALL, but add a CT Chest Abdomen Pelvis (CAP) biopsy lymph node for diagnosis.
- Neuroblastoma presentation depends on whether the tumour is abdominal or thoracic; limp and bone pain indicate bony metastasis.
On the advice of the haem/onc team, you switch the antibiotic to piperacillin/tazobactam.
A bone marrow aspiration confirms a diagnosis of ALL, and the patient is transferred urgently to the regional oncology centre and started on induction chemotherapy.
Take home messages
Many things can cause prolonged fever, and it can take skill and time to differentiate them.
The patient with unexplained prolonged fever should be admitted for serial examination, monitoring and investigations.
Keep calm and start thinking about zebras!
References
Reynolds et al. The child with prolonged fever: when to think zebras. Paediatrics and Child Health https://doi.org/10.1016/j.paed.2024.12.001
