Theme

The Child with Prolonged Fever

P. Q. L, L. GOFFIN, A. FERSTER

Paediatric Immunology/Haematology/Oncology
Rheumatology Unit
Hpital Universitaire des Enfants Reine Fabiola,
ULB, Brussels
Phuquoc.LE@huderf.be

SUMMARY
Fever is one of the most frequent reasons for parents to take their
children either to the general practitioner or to the emergency unit.
Underlying infection is the first cause of fever and its outcome is
generally good. On the other hand, prolonged fever in children
presents a challenge for paediatrician. Indeed, it can be the first
symptom of several serious illnesses requiring rapid medical
intervention. Sometimes these diseases are not diagnosed rapidly
despite exhaustive evaluation. Knowledge of the differential
diagnosis is therefore necessary to guide physicians to define the
correct etiology in order to start accurate treatments.

Introduction

- to determine the appearance of the temperature curve

- to evaluate associated symptoms including deterioration of
the physical status, nocturnal sweating, cutaneous eruption,

This should be completed by a meticulous physical

examination.

Fever is a common symptom in paediatrics and is mostly due

to infection. Fever is caused by pyrogenic cytokines acting on
the hypothalamus through prostaglandins E2 (PGE2).
Prolonged fever (PF) in a child is a special situation that
justifies a particular approach. Although the definitions of PF
differ among authors [1], by convention, PF is characterized by
daily fever that has lasted for 5 days with a temperature greater
than 38 Celsius for an infant (< 1 year) and 7 to 10 days with
a temperature greater than 38,5 Celsius for an older child.
PF of unknown origin is defined if daily fever persists for more
than 3 weeks and history, clinical examination and preliminary
investigations fail to diagnose a single illness.
PF is to be distinguished from
- Recurrent fever [2] from a single illness in which fever and
other signs and symptoms wax and wane,
- Periodic fever [3] which includes recurring episodes of illness
for which fever is the cardinal feature, and other associated
symptoms are similar and predictable, and duration is days
to weeks, with intervening intervals of weeks to months
of complete well-being. Fever episodes can have either a
clockwork presentation or have irregular periodicity.
The clinical approach to the child with prolonged fever requires
an extensive history taking with detailed dissection of the fever
history, including:
- evaluation of travel history, presence of fever in the family,
medication exposure
- to know if the temperature was measured by the parents or
by somebody else

The etiology of PF includes infections, inflammatory diseases,

neoplasms, simulated fever and the rare idiopathic PF without
any specific etiology found after numerous investigations.
Therefore the knowledge of the main causes is an essential
component in the orientation for complementary evaluation in
order to get a diagnosis as soon as possible.

Different causes of prolonged

fever in children

The first step consists of obtaining the characteristics of the
fever, and confirming or not its authenticity. An exhaustive
anamnesis is fundamental to characterize the fever in term of its
beginning, the circumstance of appearance, the schedule, the
intensity, the number of peaks occurring daily, the associated
signs and the response to treatment. It is important to rule
out simulated fever (handling thermometer) or inferred fever
(Munchausens Syndrome) by qualified hospital staff.
PF in children requires a profound search for:
- infections of viral, bacterial and parasitic origin
- malignant pathology
- inflammatory or autoimmune disease.
The causes of prolonged fever may differ according to the age
of the child.

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1. Infants and young children (< 5 years)

Infections (particularly viral infections) are the most common
cause of PF. It is important to search for urinary tract,
respiratory and ENT (ethmoiditis or mastoiditis) and
bone infections. Although uncommon, tuberculosis and
tuberculosis meningitis have to be taken into consideration
in a child with PF. In a young child with frequent infections,
an underlying immune deficiency or anatomical malformation
has to be looked for. Cyclic neutropenia may present with
recurrent episodes of PF without infectious cause.
Fever related to dehydration is easily diagnosed and
anhydrotic ectodermal dysplasia should be ruled out.
Fever of neurological origin is rare but a subdural chronic
hematoma must be excluded. PF is also described in case of
encephalopathy, or in children with cerebral malformations.
Kawasaki disease [4] is an acute febrile illness with systemic
vasculitis of unknown etiology which prognosis depends on
the development of coronary artery aneurysms. The diagnosis
is made on clinical criteria but atypical and incomplete forms
exist. Thus the diagnosis should be evoked in the presence
of fever of more than 5 days associated with a severe
inflammatory response and with increased (or increasing)
platelet counts even if other diagnostic criteria are lacking.
Kawasaki disease represents a diagnostic urgency since a
rapid treatment (before the tenth day of fever, and ideally
before the seventh day) with intravenous immunoglobulins
may prevent the development of coronary aneurysms.
Among other inflammatory diseases, systemic onset
juvenile idiopathic arthritis (JIA) [5] may be the cause of PF in
children. The fever of systemic JIA is characterized by daily
spiking fever occurring at the same moment of the day, often
accompanied by chills and severe myalgias/arthralgias and
which does not respond well to usual antipyretic treatments.
The child appears ill at the moment of fever, but may recover
very well between fever peaks. Arthritis may be absent at the
onset of systemic JIA; on the other hand one should look for
typical extra-articular features such as rash, adenopathies,
hepato-splenomegaly and serosal inflammation, as detailed
in the text on systemic JIA.
Neoplasia has to be ruled out by appropriate investigations;
especially a metastatic neuroblastoma and acute
lymphoblastic leukaemia could present with fever and poor
general condition in a young child.
Macrophage activation syndrome [6] is an unusual etiology
of PF. It represents a severe inflammatory condition caused
by uncontrolled proliferation of activated lymphocytes
and histiocytes secreting high amounts of inflammatory
cytokines. The clinical pictures include PF, hepatosplenomegaly, lymphoadenopathies, central nervous
system involvement, signs of consumptive coagulopathy,
and eventually signs of multiple organ failure, which can lead
to the death of the patient. The typical biological markers
include pancytopenia, elevated ferritin and triglycerides with
low fibrinogen and consumption coagulopathy. Increased

liver enzymes and hyponatremia are equally present. The

diagnosis is confirmed by demonstration of macrophage
proliferation with at least 5% of macrophages presenting
hemophagocytosis in a lymphoid organ (spleen, lymph
node, bone marrow). The macrophage activation syndrome
comprises a heterogeneous group of disorders of genetic,
autoimmune, malignant, dysimmunity, and toxic origin.
Appropriate treatment needs to be installed immediately.
2. Older children (> 5 years)
Infection remains a predominant cause of PF. In addition
to viral causes (infectious mononucleosis, cytomegalovirus
infection, toxoplasmosis,), urinary tract, respiratory or ENT
(in particular sinus) infections, infrequent etiologies have to
be searched for such as a deep abscess, endocarditis,
osteitis. Other uncommon infections include malaria,
hantavirus, brucellosis, visceral catscratch disease, visceral
leishmaniasis.
Malignant diseases commonly responsible for PF are acute
lymphoblastic leukaemia, lymphoma (especially Hodgkins
disease) and metastatic neuroblastoma.
Castlemans disease is an inflammatory disease caused by
a lymphocyte and plasma cell proliferation with an excessive
production of pro-inflammatory cytokines such as IL6 by
pathological lymph nodes. Both generalized/multicentric
and localized forms exist, the latter being most frequent in
children. Cure is confirmed with complete resection of the
tumoral mass.
Kawasaki disease as well as systemic onset JIA can present
with PF in an older child as well. Other rare inflammatory
conditions that may cause PF in an older child comprise
polyarteritis nodosa and other systemic vasculitides
(Takayasu Arteritis, Wegeners granulomatosis, ChurgStrauss syndrome, microscopic polyangiitis).
P
 olyarteritis nodosa is a systemic vasculitis affecting small
and medium sized vessels. In children, cardinal onset signs
and symptoms are non-specific with unexplained fevers,
asthenia, severe myalgias, weight loss, skin rash, abdominal
pain and arthralgia/arthritis mostly affecting large joints.
Typical cutaneous symptoms are painfull palpable purpura
or nodules indicating an area of arteriolar inflammation.
Additional clinical features are linked to different organs
affected by altered blood flow (skin, kidney, nervous
system, digestive system, eye, hart, ). Both central and
peripheral nervous system involvement can be seen, with
cranial neuropathy, seizures, cerebrovascular accidents and
peripheral neuropathy.
A
 t last some connective tissue diseases may be associated
with PF. Children with juvenile dermatomyositis may have low
grade fever, often with a typical skin rash and muscle fatigue.
The clinical manifestations of systemic lupus erythematosus
will be discussed further.
Inflammatory bowel disease, especially Crohns disease may
come to attention because of prolonged unexplained fever,

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most often suspicion is raised because of some abdominal

signs and stagnation of weight gain.
Acute rheumatic fever has become a rare entity. A valvular
carditis, erythema marginatum or chorea following a
streptococcal infection are very unusual situations.
Rheumatic fever has to be thought of as well in a child with
fever, polyarthralgia and an increased ESR who does not yet
fulfill the revised Jones criteria.
Finally, Langerhanscell histiocytosis may cause prolonged
fever, most often in association with polyvisceral involvement.
The diagnosis requires a biopsy with identification of the
typical Langerhans cell that stains positive for the S100
protein.

Conclusion

References

1. Long SS. Distinguishing Among Prolonged, Recurrent, and Periodic

Fever Syndromes: Approach of a Pediatric Infectious Diseases
Subspecialist. Pediatr Clin North Am 2005; 52: 811-35
2. Padeh S. Auto-inflammatory Fever Syndromes. Rheum Dis Clin
North Am 2007; 33: 585-623
3. Majeed HA. Differential diagnosis of fever of unknown origin in
children. Curr Opin Rheumatol 2000; 12: 439-44
4. Pinna GS. Kawasaki disease: an overview. Curr Opin Infec Dis
2008 ; 21: 263-70
5. Prieur AM. Rhumatologie pdiatrique. Paris : Mdecine-Sciences,
Flammarion 1999
6. Janka
GE.
Familial
and
acquired
hemophagocytic
lymphohistiocytosis. Eur J Pediatr. 2007; 166: 95-109

PF represents a major challenge for the medical practitioner

because it can be the hallmark of numerous diseases, which
need to be diagnosed rapidly and appropriately. Meticulous
history taking and thorough physical examinations are
mandatory and may have to be repeated before making a
final diagnosis. When infectious and malignant causes have
been ruled out, a wide spectrum of inflammatory and/or
autoimmune diseases has to be investigated.

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