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Recurrent Fevers in Children: Differential Diagnosis

Am Fam Physician. 2003 Feb 15;67(4):863-864.

Recurrent fevers are defined as three or more febrile episodes in a six-month period, occurring at least seven days apart, with no causative medical illness. These episodes can occur at regular or irregular intervals. John and Gilsdorf review the evaluation and differential diagnoses for recurrent fever. An overview is provided in the accompanying table.

Few diseases cause a regular pattern of recurrent fevers. The most common diagnosis associated with this fever pattern is PFAPA syndrome (i.e., periodic fever, aphthous ulcers, pharyngitis, and adenopathy). PFAPA is characterized by high fevers lasting three to six days and recurring every 21 to 28 days, accompanied by some or all of the signs noted in its name. The syndrome usually occurs in children younger than five years who present with regular fevers and cervical adenopathy. Aphthous ulcers, which are usually small and relatively painless, are the symptom most likely to be missed.

Differential Diagnosis in the Child with Recurrent Fever

Fever occurring at regular intervals

Fever occurring at irregular/unpredictable intervals

Fever typically occurs at regular intervals

Infectious

PFAPA syndrome (21 to 28 days)*

Viral

Cyclic neutropenia (21 to 28 days)

Repeated viral infections*

Relapsing fever (Borrelia spp. other than Borrelia burgdorferi, 14 to 21 days)

Epstein-Barr virus

Parvovirus B19

Undiagnosed cause*

Herpes simplex viruses 1 and 2 (?)

Fever occasionally occurs at regular intervals

Bacterial/mycobacterial

Familial Mediterranean fever (7 to 28 days)

Repeated bacterial infections/occult bacterial infection* (must exclude urinary tract infection) Relapsing fever (Borrelia spp. Other than B. burgdorferi) Chronic meningococcemia Occult dental abscess Brucellosis Yersinia enterocolitica Mycobacteria, nontuberculous (e.g., Mycobacterium chelonai)

Hyper-IgD syndrome (14 to 28 days)

Epstein-Barr virus (6 to 8 weeks)

Undiagnosed cause*

Parasitic

Relapsing malaria (Plasmodium vivax, Plasmodium ovale)

Reactivation of Plasmodium malariae.

Inflammatory/immunologic

Inflammatory bowel disease, usually Crohn's disease*

Still's disease (systemic-onset juvenile rheumatoid arthritis)*

Behçet's disease

Hereditary periodic fevers

Familial Mediterranean fever

Hyper-IgD syndrome

TRAPS

Familial cold urticaria

Muckle-Wells syndrome

Neoplasm

Lymphoma

Other

Undiagnosed cause*

Drug fever

Factitious fevers

Central nervous system abnormalities (hypothalamic dysfunction, agenesis of corpus callosum)


PFAPA = periodic fever, aphthous ulcers, pharyngitis, and adenopathy; TRAPS = tumor necrosis factor receptor–associated periodic syndrome.

*—Common cause of recurrent fever.

Adapted with permission from John CC, Gilsdorf JR. Recurrent fever in children. Pediatr Infect Dis J 2002;21:1072.

Differential Diagnosis in the Child with Recurrent Fever

View Table

Differential Diagnosis in the Child with Recurrent Fever

Fever occurring at regular intervals

Fever occurring at irregular/unpredictable intervals

Fever typically occurs at regular intervals

Infectious

PFAPA syndrome (21 to 28 days)*

Viral

Cyclic neutropenia (21 to 28 days)

Repeated viral infections*

Relapsing fever (Borrelia spp. other than Borrelia burgdorferi, 14 to 21 days)

Epstein-Barr virus

Parvovirus B19

Undiagnosed cause*

Herpes simplex viruses 1 and 2 (?)

Fever occasionally occurs at regular intervals

Bacterial/mycobacterial

Familial Mediterranean fever (7 to 28 days)

Repeated bacterial infections/occult bacterial infection* (must exclude urinary tract infection) Relapsing fever (Borrelia spp. Other than B. burgdorferi) Chronic meningococcemia Occult dental abscess Brucellosis Yersinia enterocolitica Mycobacteria, nontuberculous (e.g., Mycobacterium chelonai)

Hyper-IgD syndrome (14 to 28 days)

Epstein-Barr virus (6 to 8 weeks)

Undiagnosed cause*

Parasitic

Relapsing malaria (Plasmodium vivax, Plasmodium ovale)

Reactivation of Plasmodium malariae.

Inflammatory/immunologic

Inflammatory bowel disease, usually Crohn's disease*

Still's disease (systemic-onset juvenile rheumatoid arthritis)*

Behçet's disease

Hereditary periodic fevers

Familial Mediterranean fever

Hyper-IgD syndrome

TRAPS

Familial cold urticaria

Muckle-Wells syndrome

Neoplasm

Lymphoma

Other

Undiagnosed cause*

Drug fever

Factitious fevers

Central nervous system abnormalities (hypothalamic dysfunction, agenesis of corpus callosum)


PFAPA = periodic fever, aphthous ulcers, pharyngitis, and adenopathy; TRAPS = tumor necrosis factor receptor–associated periodic syndrome.

*—Common cause of recurrent fever.

Adapted with permission from John CC, Gilsdorf JR. Recurrent fever in children. Pediatr Infect Dis J 2002;21:1072.

Children with PFAPA syndrome are well between episodes and relatively well even during episodes. Laboratory tests are helpful only during episodes, when leukocytosis or elevated erythrocyte sedimentation rate (ESR) can be detected. The cause of PFAPA is unknown, although viral or autoimmune etiologies have been suggested. Treatment at the beginning of the symptomatic period with a single dose of prednisone (2 mg per kg) relieves symptoms. Use of prophylactic cimetidine or tonsillectomy also may improve symptoms in some children.

Other causes of recurrent fevers include rare diseases such as cyclic neutropenia (which has symptoms similar to those of PFAPA) or relapsing fever, or uncommon manifestations of common diseases such as Epstein-Barr virus infection. Diagnosis of cyclic neutropenia requires obtaining frequent leukocyte counts during febrile and nonfebrile periods to document a decline in the absolute neutrophil count (less than 500 per mm3 [0.5 × 109 per L]), with recovery to normal shortly after. Marrow examination done at the time of neutropenia reveals myeloid line maturation arrest. In children who have severe symptoms with cyclic neutropenia, granulocyte colony-stimulating factor decreases the duration of neutropenia and the resultant risk of infection.

Recurrent fevers that occur at irregular intervals have a lengthy differential diagnosis. Infectious causes can include viruses, bacteria, and parasites. Fever without any other sign or symptom is more common with viral infections than with bacterial infections. Fungal infections have not been reported to cause recurrent fevers in healthy children. Inflammatory or autoimmune diseases, including inflammatory bowel disease, juvenile rheumatoid arthritis, and Behçet's disease, as well as hereditary periodic fevers, lymphoma, and factitious fever, should be considered. ESR testing is useful in distinguishing inflammatory from hereditary disorders.

The laboratory work-up in children with recurrent fever depends on the history and physical examination. The apparently healthy child needs only a complete blood cell count (CBC) with differential and platelet count, and ESR and C-reactive protein testing. Urine cultures are also useful. If the child appears ill, blood cultures should be obtained, with additional tests as indicated by potential exposure, clinical history, and physical examination. Children with normal initial evaluations and no additional signs or symptoms do not require further testing. Recurrent fevers with no defined underlying cause have a very favorable prognosis.

The authors conclude that recurrent fever often occurs without any defined etiology. Diagnostic testing should be limited, depending on a careful history and focused physical examination. Careful follow-up will help in the early identification of other presenting symptoms of serious disease. Recurrent fever in children usually resolves without any long-term adverse effects.

John CC, Gilsdorf JR. Recurrent fever in children. Pediatr Infect Dis J. November 2002;21:1071–80.


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