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The Child with Prolonged Fever

p. Q. lÊ, l. goFFin, a. Ferster

paediatric immunology/haematology/oncology rheumatology unit

hôpital universitaire des enfants reine Fabiola, ulB, Brussels

phuquoc.le@huderf.be

- 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.

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 (Munchausen’s 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.

Introduction

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

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.

Theme

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Theme

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, hepato-splenomegaly, 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 Hodgkin’s disease) and metastatic neuroblastoma.

• Castleman’s 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, Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis).

Polyarteritis 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.

At 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 Crohn’s 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, Langerhans’cell 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

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.

Theme

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 pédiatrique. Paris : Médecine-Sciences, Flammarion 1999

6. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr. 2007; 166: 95-109

References