1. Antoon JW, Potisek NM, Lohr JA. Pediatric fever of unknown origin. Pediatr Rev. 2015 Sep;36(9):380-90; quiz 391. [PMID: 26330472].
  2. Bula-Rudas FJ, Rathore MH, Maraqa NF. Salmonella infections in childhood. Adv Pediatr. 2015 Aug;62(1):29-58. [PMID: 26205108].
  3. Jacobs RF, Schutze GE. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children. Clin Infect Dis. 1998;26(1):80. [PMID: 9455513].
  4. Ayusawa M, Sonobe T, Uemura S, et al, Kawasaki Disease Research Committee. Revision of diagnostic guidelines for Kawasaki disease (the 5th revised edition). Pediatr Int. 2005;47(2):232. [PMID: 15771703].
  5. Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med. 2012 Jul 26;367(4):348-61. [PMID: 22830465].

Image Sources

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Contributor Information


Jamie Lien, MD
Associate Clinical Professor of Pediatrics
University of California, San Diego School of Medicine
Faculty, Department of Pediatrics
Rady Children's Hospital
San Diego, CA

Disclosure: Jamie Lien, MD, has disclosed no relevant financial relationships.


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Fever of Unknown Origin: Cases in Pediatrics

Jamie Lien, MD  |  March 10, 2016

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Slide 1

The term fever of unknown origin (FUO) in pediatrics has had varying definitions in the literature, with duration of fever ranging, depending on the definition, from 5 to 21 days. However, the increased availability of rapid diagnostic testing has shortened the period of time before which standard FUO etiologies are seriously considered; a commonly accepted definition of FUO in pediatrics is now a fever that has lasted for at least 8 days and for which no clear source is demonstrable. Fever, in this context, is usually specified as a temperature of higher than either 100.4°F (38.0°C) or 101°F (38.3°C), again depending on the definition.[1] Usually, FUO is an uncommon presentation of a common disease.

Slide 2

The range of etiologies of FUO in children is quite extensive, including infectious, oncologic, autoimmune, genetic, factitious, and iatrogenic causes. A thorough history and physical examination can help to narrow the differential diagnosis and guide laboratory and radiographic evaluation.

Slide 3

A 4-year-old girl with no significant past medical history presents to the emergency department (ED) with 7 days of fever with intermittent vomiting and abdominal pain, as well as 2 days of nonbloody diarrhea. Her family emigrated from India to the United States 12 days ago. The patient has been seen in urgent care centers and EDs four times since becoming ill. Her immunization history includes all recommended vaccines in India, including those for hepatitis A and hepatitis B and two doses of typhoid vaccine, though she is due for a typhoid booster soon.

On examination, the patient's vital signs are normal. She appears well and is well hydrated, with mild abdominal tenderness in the upper quadrants. Laboratory evaluation reveals mild anemia, mild thrombocytopenia, bandemia, elevated C-reactive protein (CRP), and mildly elevated transaminases. Cultures of the blood and stool grow the organism pictured in the slide.

Which of the following is the most likely cause of this patient's symptoms?

  1. Malaria
  2. Hepatitis B
  3. Hepatitis A
  4. Infection with Salmonella enterica subsp enterica serovar Typhi
  5. Infection with Escherichia coli

Image courtesy of the Centers for Disease Control and Prevention.

Slide 4

Answer: D. Salmonella enterica subsp enterica serovar Typhi.

Enteric fever is caused by infection of the bloodstream and intestinal tract with S enterica subsp enterica serovar Typhi (typhoid fever) or S enterica subsp enterica serovar Paratyphi A, B, or C (paratyphoid fever). Affected individuals have severe systemic illness with fever and abdominal pain, with onset 5-21 days after ingestion of the causative agent in contaminated food or water. Classic manifestations include relative bradycardia, or pulse-temperature dissociation, and faint salmon-colored macules on the trunk and abdomen ("rose spots"). Additional symptoms can include diarrhea or constipation, hepatomegaly, intestinal bleeding, perforation, and neurologic abnormalities.

The World Health Organization (WHO) estimates that 16-33 million cases of typhoid fever, causing 500,000-600,000 deaths, occur worldwide each year. In the United States, approximately 200-300 cases occur annually, the majority of which are acquired while traveling in endemic areas (shown). The WHO recommends the use of typhoid vaccine in these areas.[2] This case highlights the importance of obtaining a travel history in patients with FUO.

Image courtesy of World Health Organization.

Slide 5

A 6-year-old boy presents to his primary care physician with 9 days of fever and new-onset left lateral thigh pain beginning that morning. He was seen at an earlier point during this illness and was given an antibiotic for acute otitis media, with no reduction in his fever. The patient develops left knee pain and is sent to the ED for evaluation the next day. Physical examination and radiography of the pelvis, femur, knee, and tibia/fibula yield normal results, but laboratory assessment reveals elevated levels of markers of inflammation (shown). Magnetic resonance imaging (MRI) of the left knee is performed and shows no evidence of inflammation. A few days later, although examination findings remain normal, the patient continues to be febrile, and his inflammatory markers remain elevated. Blood cultures have not grown any organisms. MRI of the pelvis and the entire left lower extremity is ordered. The patient is known to have cats at home.

Slide 6

MRI of the pelvis shows multifocal pelvic osteomyelitis, with a septic left sacroiliac joint (thin arrow) and an associated 2.4-cm paraspinal muscular abscess and myositis (thick arrow). After MRI is performed, closer musculoskeletal examination reveals tenderness with lateral compression and stressing of the sacroiliac joint, though the patient maintains full range of motion (ROM) of the hip and a normal gait. The patient undergoes incision and drainage of the left paraspinal abscess and the left iliac bone. Routine bacterial cultures are negative, but polymerase chain reaction (PCR) testing confirms the cause of this patient's symptoms, supported by serologic studies for this organism.

Which of the following is the most likely causative organism?

  1. Staphylococcus aureus
  2. Group A streptococcus
  3. Kingella kingae
  4. Salmonella
  5. Bartonella henselae

Image courtesy of Jamie Lien, MD.

Slide 7

Answer: E. Bartonella henselae.

Cat-scratch disease, or bartonellosis, is caused by infection with B henselae or, less frequently, Bartonella quintana. Cats serve as the natural reservoir for these organisms, and most cases of cat-scratch disease result from a cat scratch or bite or from a flea bite. The disease is usually characterized by self-limited regional lymphadenopathy, but it can disseminate to atypical locations, including the liver, the spleen, the eyes, the central nervous system (CNS), and the musculoskeletal system. In one study, bartonellosis was found to be the third most common infectious cause of FUO in children.[3] It should be considered in any child with prolonged fever, particularly in those with probable cat exposure. A careful history that elicits any previous or current animal exposure can help to guide investigation of FUO.

Image courtesy of Dreamstime.

Slide 8

A 14-year-old boy presents to his primary care physician with 8 days of right-knee pain and intermittent tactile fever. He has been limping but otherwise feels well. He denies any history of trauma. Physical examination is notable for mild swelling and increased warmth over the right knee, tenderness with palpation of the distal femur, and inability to fully extend the knee because of pain. Plain radiographs of the right knee show a small joint effusion (arrow) with soft-tissue swelling. No bony abnormalities are identified.

Which of the following is the most appropriate next step in management?

  1. Obtaining serum levels of inflammatory markers
  2. Radiography of the contralateral knee
  3. MRI of the knee
  4. Aspiration of the knee joint
  5. Referral to an orthopedist

Images courtesy of Jamie Lien, MD.

Slide 9

Answer: A. Obtaining serum levels of inflammatory markers.

The patient's presentation raises concerns about possible septic arthritis or osteomyelitis, as well as malignancy and rheumatologic disorders. Accordingly, laboratory tests are obtained, with the results shown in the slide.

Which of the following is the most appropriate diagnostic study to perform next?

  1. Aspiration of the knee joint
  2. Incision and drainage of the distal femur
  3. Bone marrow biopsy
  4. Bone scan
  5. Distal femur biopsy
Slide 10

Answer: C. Bone marrow biopsy.

The blood test results indicate a markedly significant leukocytosis with abnormal presence of immature white blood cells (blasts) in the peripheral circulation. The high lactate dehydrogenase level indicates increased cell turnover. An elevated uric acid value in this setting implies tumor lysis.

Bone marrow biopsy (shown) reveals hypercellular marrow with diffuse leukemic infiltrate, consistent with persistent acute myeloid leukemia. Acute leukemia is the most common cancer in children. Initial presenting symptoms may be nonspecific and may include fever, malaise, musculoskeletal pains, lymphadenopathy, hepatosplenomegaly, and bleeding. Maintaining a high level of suspicion for this condition can facilitate rapid diagnosis and initiation of appropriate management.

Image courtesy of Wikimedia Commons | Paulo Henrique Orlandi Mourao.

Slide 11

A 15-month-old girl presents to the ED with 8 days of fever. She has already undergone blood and urine testing, as well as chest radiography, but no source for her fever has been identified. Four days ago, she developed a prominent bump on the left side of her neck. Two days ago, she developed red eyes, red lips and tongue, redness in her hands and feet, a rash on her abdomen, and increased irritability. Laboratory studies are obtained, with the results shown in the slide.

Which of the following is the most likely diagnosis?

  1. Kawasaki disease
  2. Lymphoma
  3. Bacterial lymphadenitis
  4. Pyelonephritis
  5. Streptococcal pharyngitis
Slide 12

A. Kawasaki disease.

Kawasaki disease is a vasculitis that primarily affects medium-sized muscular arteries. It is predominantly seen in children, and if it is left untreated, it can lead to serious cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease in children in the United States. The etiology is currently unknown. A formal diagnosis of Kawasaki disease requires the presence of fever lasting at least 5 days in conjunction with at least four of the five criteria listed in the slide. Atypical or incomplete presentations are not uncommon, however, and often the diagnosis can be made before the patient has had 5 full days of fever.[4] Although no definitive diagnostic test for Kawasaki disease has yet been developed, certain laboratory findings can assist in the diagnosis of this condition. Systemic inflammation leads to elevations in CRP and erythrocyte sedimentation rate (ESR), and thrombocytosis may occur. Additional abnormalities may include a normocytic, normochromic anemia; sterile pyuria; elevations in alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), or both; hypoalbuminemia; and hyponatremia. Coronary artery dilatation on echocardiography supports the diagnosis.

Many other childhood illnesses are easily confused with Kawasaki disease, particularly in younger children and those with incomplete presentations of Kawasaki disease. Timely diagnosis depends on a high index of suspicion and repeated histories and physical examinations.

Images courtesy of the Kawasaki Disease Foundation.

Slide 13

A 5-year-old girl residing in Mexico presents with a history of daily fever for 2 months. She developed left knee pain 1 year ago, at which time she was diagnosed with juvenile idiopathic arthritis. Her arthritis has been managed with daily methotrexate and prednisolone. The patient's parents report that she has not been able to walk for the past 6 months and has lost 17 kg over the past 1 month. In the preceding 5 days, she has complained of daily right-side headache and has had vomiting, fatigue, and intermittent confusion. On physical examination, the patient is a thin, small girl who is in no acute distress. Her vital signs are within normal limits, but her weight is below the first percentile for her age, and her height is at approximately the fourth percentile. The patient is holding her left lower extremity in full flexion at the hip and the knee, and she refuses any attempt at ROM; she cries with pain upon palpation over the knee. No rash is noted. At this point, the most likely diagnoses for this patient include infectious, rheumatologic, and oncologic conditions (shown).

Slide 14

MRI of the pelvis and left lower extremity (left) and of the brain (right) is done. Which of the following diagnoses is most strongly supported by the MRI findings?

  1. Systemic lupus erythematosus
  2. Juvenile idiopathic arthritis
  3. Leukemia
  4. Tuberculosis
  5. HIV infection

Images courtesy of Jamie Lien, MD.

Slide 15

Answer: D. Tuberculosis.

MRI of the pelvis (left) shows a diffuse process centered on the left hip that involves the acetabulum (medium yellow arrow), the femoral head (thin yellow arrow), and the proximal femur. Areas of lack of enhancement within these bones indicate intraosseous abscess. A large joint effusion is noted on the left (thick yellow arrow). A rounded fluid collection with an enhancing rim is seen posterior to the hip joint (dotted yellow arrow). These findings indicate an infectious etiology, with osteomyelitis in all the bones about the left hip joint, synovial inflammation, and an abscess posteriorly. MRI of the brain (right) shows abnormal enhancement about the circle of Willis and its cisterns (arrow), which is consistent with basilar meningitis. This combination of findings, in conjunction with the history, is highly suspicious for tuberculosis.

Images courtesy of Jamie Lien, MD.

Slide 16

Lumbar puncture yields cerebrospinal fluid with a low glucose concentration, a high protein concentration, and lymphocytic pleocytosis (shown). Biopsy of the synovium and bone of the left hip and the femur demonstrates severe necrotizing granulomatous inflammation, with scattered acid-fast bacilli. Mycobacterium tuberculosis PCR assay of these biopsy specimens yields positive results. In children younger than 5 years, tuberculosis can progress rapidly from latent infection to active disease. Pulmonary disease is common, but extrapulmonary disease can occur in many sites, most frequently the superficial lymph nodes and the CNS. Other sites that may be involved include the pleura, the pericardium, the abdomen, the joints and vertebrae, the skin, the kidneys, and the eyes. Severe disease manifestations, such as miliary tuberculosis and meningitis, are seen more commonly in young children.[5]

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