Fever of Unknown Origin Synonyms and related keywords: fever wit

1. Fever of Unknown OriginSynonyms and related keywords: fever without a focus, fever of unknown etiology, fever without a source, fever without localizing signs, fever withiout a focus, pediatric fever.  V. MIH�L

3. Definition of FUO Fever is defined as a rectal temperature exceeding 38�C (100.4�F). Direct the initial evaluation of these patients toward identifying occult bacteremia or other serious bacterial infections. Address the following questions: What laboratory studies are indicated for various age ranges? Which patients need in-depth evaluation and treatment? Which patients need treatment with antibiotics? Which patients should be hospitalized? Which patients can be sent home safely, and what follow-up is appropriate for them? Are the diagnosis and treatment modalities for each patient cost-effective? What is the potential morbidity associated with testing and treatment? What are the parental (and patient) preferences for testing and treatment?

4. Background Infants or young children who have fevers with no obvious source of infection present a diagnostic dilemma. Healthcare providers see these patients on a daily basis. As many as 20% of childhood fevers have no apparent cause. A small but significant number of these patients may have a serious bacterial infection�the risk is greatest among febrile infants and children younger than 36 months�making proper diagnosis and management important. Physical examination and patient history do not always identify patients with occult bacteremia or serious bacterial infection. Serious infections that are not recognized promptly and treated appropriately can cause significant morbidity or mortality.

5. FUO This article focuses primarily on infants and young children aged 2-36 months and reflects the significant changes in the care of the febrile infant and child over the past 10 years. The article Fever in the Young Infant addresses the diagnosis and treatment of febrile infants younger than 2 months.

6. Causes of FUO #1 cancer, #2 infection (#1 in children), collagen-vascular disease, drugs (barbiturates, antibiotics, antihypertensives, antiarrhythmic, phenytoin, antihistamine, salicylates, cimetidine, bleomycin, allopurinol), factitious, pulmonary embolism, inflammatory bowel disease, subacute thyroiditis, retroperitoneal hematoma most children have common illness with uncommon presentation most common infectious FUO in children - salmonellosis, rickettsial disease, infectious mononucleosis, cytoplasmic inclusion body disease, hepatitis, TB PFABA syndrome with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (J Pediatr 1999 Jul;135(1):15, 98 in J Watch 1999 Aug 15;19(16):131), editorial can be found in J Pediatr 1999 Jul;135(1):1 consider Kawasaki disease in children with prolonged unexplained fever (Pediatr Infect Dis J 2004 Aug;23(8):782 in Pediatric Notes 2004 Oct 7;28(41):164)

8. Pathophysiology Meningitis and sepsis are serious etiologies of fever in infants and young children. Neonates' immature immune systems place them at greater risk of systemic infection. Hematogenous spread of infection is most common in this age group or in patients who are immunocompromised. For these same reasons, infants who have a focal bacterial infection have a greater risk of developing sepsis. The following are among the most common bacterial etiologies of serious bacterial infection in this age group: Streptococcus pneumoniae Group B streptococci Neisseria meningitidis Haemophilus influenzae type b Listeria monocytogenes Escherichia coli Approximately 2.5-3% of highly febrile children younger than 3 years develop occult bacteremia, which typically is caused by S pneumoniae. Viral infections are common in the young child as well; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever.

9. Frequency   Fever accounts for 10-20% of pediatric visits to health care providers. Mortality/Morbidity: Patients with no easily identified source of infection have a small but significant risk of a serious bacterial infection. If not recognized and treated appropriately and promptly, this can cause morbidity or mortality. Age: This article focuses on the diagnosis and treatment of febrile children aged 2-36 months. 

10. History I Obtaining an accurate history from the parent or caregiver is important; the history obtained should include the following information: Fever history: What was child's temperature prior to presentation, and how was temperature measured? Consider fever documented at home by a reliable parent or caregiver the same as fever found on presentation. (Accept parental reports of maximum temperature.) Fever at presentation: If the physician believes the infant has been bundled excessively, and if a repeat temperature taken 15-30 minutes after unbundling is normal, the infant should be considered afebrile. Always remember that normal or low temperature does not preclude serious, even life-threatening, infectious disease.

11. History II Current level of activity or lethargy Activity level prior to fever onset (ie, active, lethargic) Current eating and drinking pattern Eating and drinking pattern prior to fever onset Appearance: Fever sometimes makes a child appear rather ill. Vomiting or diarrhea Ill contacts Medical history Immunization history (especially recent immunizations) Urinary output - Number of wet diapers

12. Physical I While performing a complete physical examination, pay particular attention to assessing hydration status and identifying the source of infection. Physical examination of every febrile child should include the following: Record vital signs. Temperature: Rectal temperature is the standard. Temperature obtained via tympanic, axillary, or oral methods may not truly reflect the patient's temperature. Pulse rate Respiratory rate Blood pressure

13. Physical II Measure pulse oximetry levels. Pulse oximetry may be a more sensitive predictor of pulmonary infection than respiratory rate in patients of all ages, but especially in infants and young children. Pulse oximetry is mandatory for any child with abnormal lung examination findings, respiratory symptoms, or abnormal respiratory rate, although keep in mind that respiratory rate increases when children are febrile. Record an accurate weight on every chart. All pharmacologic and procedural treatments are based on the weight in kilograms. In urgent situations, estimating methods (eg, Broselow tape, weight based on age) may be used.

14. Physical III During the examination, concentrate on identifying any of the following: Toxic appearance, which suggests possible signs of lethargy, poor perfusion, hypoventilation or hyperventilation, or cyanosis (ie, shock) A focus of infection that is the apparent cause of the fever Minor foci (eg, otitis media [OM], pharyngitis, sinusitis, skin or soft tissue infection) Identifiable viral infection (eg, bronchiolitis, croup, gingivostomatitis, viral gastroenteritis, varicella, hand-foot-and-mouth disease) Petechial or purpuric rashes, often thought to be associated with invasive bacteremia Purpura, which is associated more often with meningococcemia than is the presence of petechiae alone

15. The Yale Observation Scale For all patients aged 3-36 months, management decisions are mostly based on the degree of toxicity and the height of temperature. The Yale Observation Scale is a reliable method for determining degree of illness. It consists of 6 variables: quality of cry, reaction to parent stimulation, state variation, color, hydration, and response. A score of 10 or less has a 2.7% risk of serious bacterial infection. A score of 16 or greater has a 92% risk of serious bacterial infection. Regarding the height of temperature, Hoberman et al found that 6.5% of patients with a temperature of 39.0�C (102.2�F) or more had a UTI and that white females with that temperature had a 17% incidence of UTI (Hoberman, 1994). In this age group, the prevalence of bacteremia correlates with the height of fever. Children with temperatures from 39-39.5�C (102.2-103�F) have an approximate 2-4% risk of having occult bacteremia. Those with temperatures higher than 39.5�C (103�F) have an approximate 5% chance of having occult bacteremia.

17. Causes I Several common bacteria cause serious bacterial infections (SBI). S pneumoniae S pneumoniae is the leading cause of nearly all common bacterial upper respiratory tract infections (eg, pneumonia, sinusitis, OM). This organism is the most common cause of meningitis in the United States. It is the most common cause of occult bacteremia. N meningitidis H influenzae type b L monocytogenes E coli

18. Causes II E coli E coli is the most common cause of urinary tract infections (UTIs). Among febrile children with UTIs, 75% have pyelonephritis, with consequences that, if missed, include renal scarring in 27-64% of patients, a 23% risk of hypertension, a 10% risk of renal failure, and a 13% risk of preeclampsia as adults. Approximately 13-15% of end-stage renal disease is believed to be related to undertreated childhood UTIs.

19. Lab Studies I   Recommended laboratory studies for children with fever of unknown etiology are based upon the child's appearance, age, and temperature. (Begin IV or IM antibiotic administration for all infants who appear ill once urine and blood specimens are obtained. Perform the following for children who do not appear toxic: Perform a complete blood count (CBC) with manual differential. Draw and hold blood cultures, pending receipt of CBC results. Send blood culture for analysis if white blood cell (WBC) count exceeds 15,000 or if absolute neutrophil count (ANC) exceeds 10,000. Perform urinalysis (UA) by bladder catheterization and urine culture based on the following criteria: All males younger than 6 months and all uncircumcised males younger than 12 months All females younger than 24 months and older female children if symptoms suggest a UTI Consider cerebrospinal fluid (CSF) studies and culture. (Obtain CSF if meningitis is suspected.) Consider obtaining a stool culture to measure fecal WBCs and stool guaiac for diarrhea.

20. Lab Studies II Perform the following for children who appear toxic: Perform a CBC with manual differential. Send blood cultures. Consider obtaining a chest radiograph. Chest radiography should be performed for patients with a WBC count greater than 20,000. Perform UA by bladder catheterization and urine culture based on the following criteria: All males younger than 6 months and all uncircumcised males younger than 12 months All females younger than 24 months and older female children if symptoms suggest a UTI Obtain CSF and perform studies and culture if any suspicion of meningitis exists. (Administer antibiotics before performing the lumbar puncture [LP] if any delay is anticipated.) Consider obtaining a stool culture to measure fecal WBCs and stool guaiac for diarrhea. Admit these patients for further treatment; pending culture results, administer parenteral antibiotics (see Treatment).

21. Imaging Studies   Chest radiography is part of any thorough evaluation of a febrile child. Chest radiography is indicated when the patient has tachypnea, retractions, focal auscultatory findings, or oxygen saturation level (SO2) on room air of less than 95%. Although viral etiologies are considered the cause of most pediatric pneumonias, 51% of pediatric patients with pneumonia have serologic evidence of bacterial infection. Chest radiographs should be obtained if WBC is >20,000. One study found a high correlation with WBC greater than 20,000 and pneumonia, even with a lack of clinical findings suggestive of pneumonia.

22. Medical Care For children who appear ill, conduct a complete evaluation to identify occult sources of infection. Follow the evaluation with empiric antibiotic treatment and admit the patient to a hospital for further monitoring and treatment pending culture results. Patients aged 2-36 months may not require admission if they meet the following criteria: Patient was healthy prior to onset of fever. Patient has no significant risk factors. Patient appears nontoxic and otherwise healthy. Patient's laboratory results are within reference ranges defined as low risk. Patient's parents (or caregivers) appear reliable and have access to transportation if the child's symptoms should worsen.

24. ROCHESTER LOW RISK CRITERIA <60 DAYDagan R et al., J Ped 1988; 112: 355-60 Infant appears well, non-toxic Infant has been previously well * born at term (>37 weeks) * no antenatal or perinatal antimicrobial therapy * no treatment for unexplaind hypebilirubinemia * not hospitalized longer than the mother at birth * no previous hospitalization * no recent antibiotic use * no chronic or underlying diseases Infant has no evidence of bacterial infection * no skin, sift tissue, bone, joint, or ear infection The following laboratotry parameters are met: * WBC count 5000-15000/mm3 * absolute band count <1500 * urinanalysis WBC count <10/hpf * stool WBC count <5/hpf(if infant has diarrhea)

25. Febrile infants aged 1-2 months I Provide a full evaluation and conservative treatment (including possible hospital admission for close monitoring and parenteral antibiotic administration) for any febrile infant who appears ill. Febrile infants who appear healthy and have no obvious source of infection require further evaluation before disposition is decided. High-risk patients in this age group are patients with a significant medical history (eg, premature infants, infants with prolonged neonatal intensive care unit stays, those who had complicated births, those with congenital heart disease).

26. Febrile infants aged 1-2 months II Low-risk patients in this age group are previously healthy infants who do not appear toxic and who exhibit no focal bacterial infection on physical examination (excluding otitis media). Consider the child's home environment (ie, social situation, presence of a reliable caregiver, availability of transportation and telephone) before placing an infant in the low-risk group. Laboratory test results for a low-risk designation must include the following: Normal UA results (ie, negative nitrite findings and/or <10 WBC/high-power field [hpf]) WBC count of 5000-15,000 If diarrhea is present, no heme and few to no WBCs in stool CSF with fewer than 8 WBC/mm3 in bloodless specimen Negative CSF Gram stain findings Bands not exceeding 20% of neutrophils No infiltrate on chest radiograph, if performed

27. Treatment Parenteral antibiotics are the drugs of choice to treat febrile or ill-appearing neonates. Selection of medications depends upon the patient's age. Coverage for Listeria with ampicillin is essential for infants younger than 6 weeks. Typically, cefotaxime or gentamicin is added (ceftriaxone may be avoided because of bilirubin displacement from serum protein-binding sites, but this is not universally recommended nor practiced). Treatment of fever in this age group is somewhat controversial.

28. Medical/Legal Pitfalls   The biggest pitfall is not considering the possibility that a febrile infant has a potentially life-threatening illness. If not treated promptly, a small percent of febrile infants who have no obvious source of serious bacterial infection may suffer serious sequelae or death. Physicians who approach their patients as if this is a possibility and who provide appropriate evaluation and treatment are doing their best to avoid a poor outcome. Stress to parents and caregivers the importance of follow-up care after patients are discharged. Also stress that an infant whose symptoms worsen should be evaluated prior to the scheduled follow-up appointment or taken to the nearest emergency department for treatment.

29. Treatment I Treatment recommendations for children with fever of unknown etiology are based upon the child's appearance, age, and temperature. For children who do not appear toxic, treatment recommendations are as follows: Consider no antibiotics; however, if ANC is greater than 10,000, administer ceftriaxone (50 mg/kg/dose). Schedule a follow-up appointment within 24-48 hours and instruct parents to return with the child sooner if the condition worsens. Hospital admission is indicated for children whose conditions worsen or whose evaluation findings suggest a serious infection

30. Treatment II For children who appear toxic, treatment recommendations are as follows: Admit child for further treatment; pending culture results, administer parenteral antibiotics. Initially administer ceftriaxone, cefotaxime, or ampicillin/sulbactam (50 mg/kg/dose).

31. Consultations, Diet, Activity Consultations: The need to consult with specialists depends upon the specialty of the physician who initially evaluated the patient and the ultimate source of fever. Typically, general pediatricians easily manage febrile infants on both an inpatient and outpatient follow-up basis. Diet: Patient tolerance is the only restriction on diet. Physicians should monitor intake and output as an indication of the patient's status because these measurements may provide the first evidence of a disturbance that indicates illness. Activity: Patient tolerance also determines activity level, which should be monitored for changes (eg, lethargy, irritability).

32. Review of Systems (ROS) prolonged fever and weight loss (cancer) myalgias, arthralgias (connective tissue disease) dyspnea, cough (TB, multiple pulmonary emboli, sarcoidosis) abdominal pain (intra-abdominal abscess, IBD, cancer)

39. Imaging studies PET scan may be useful in fever of unknown origin; 58 patients with documented fever > 3 weeks and no diagnosis after 3 days of in-hospital evaluation underwent positron emission tomography using 18-F-fluorodeoxyglucose, PET scan was abnormal in 46 patients and helped determine diagnosis in 24; 40 patients had both PET scans and gallium scans, both suggested diagnosis in 10, PET scan suggested diagnosis in an additional 4 (Clin Infect Dis 2001 Feb;32(2):191 in J Watch 2001 Mar 1;21(5):43) Society of Nuclear Medicine procedure guidelines for 111-indium-leukocyte scintigraphy for suspected infection/inflammation can be found at National Guideline Clearinghouse 2005 Jul 25:7088 Society of Nuclear Medicine procedure guidelines for 99m Tc-exametazine (HMPAO)-labeled leukocyte scintigraphy for suspected infection/inflammation can be found at National Guideline Clearinghouse 2005 Jul 25:7087 Society of Nuclear Medicine procedure guideline for gallium scintigraphy in inflammation can be found at National Guideline Clearinghouse 2005 Jul 25:7086 American College of Radiology (ACR) Appropriateness Criteria for fever without source (pediatric) can be found at National Guideline Clearinghouse 2006 Apr 14:8602

40. Empiric antibiotic regimens for children with sepsis, including possible meningitis  early neonatal sepsis (0-4 wks) most likely caused by group B streptococci, aminoglycoside-susceptible coliform bacilli or Listeria monocytogenes; empirical therapy includes ampicillin and gentamicin; alternative would be ampicillin and cefotaxime or ceftriaxone with cefotaxime preferred since ceftriaxone can displace bilirubin and worsen hyperbilirubinemia (Pediatr 198;80:873) late-onset neonatal sepsis (4-8 weeks) includes group B strep and coliform bacilli plus Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae; older infants can be treated with ampicillin with cefotaxime or ceftriaxone in older infant and child (8 weeks - 12 years), most likely organisms are pneumococcus, meningococcus, H. flu, group A strep, gram-negative bacilli, S. aureus; cefotaxime or ceftriaxone is suggested initial therapy; alternative is ampicillin and chloramphenicol (chloramphenicol levels required)

41. Empiric antibiotic regimens for children with sepsis, including possible meningitis  > 12 years most likely organisms are pneumococcus, S. aureus, meningococcus, group A strep, gram-negative bacilli; initial choice is ampicillin or penicillin G; alternatives include cefotaxime, ceftriaxone, chloramphenicol (chloramphenicol levels required) add vancomycin if suspected pneumococcal meningitis; history of central venous catheter or recent NICU admission (to cover methicillin-resistant Staphyloccus epidermidis); or risk of methicillin-resistant S. aureus add clindamycin or metronidazole if intra-abdominal infection suspected

43. Examples of Clinical or Research Applications To detect sites of infection/inflammation in patients with fever of unknown origin To localize an unknown source of sepsis and to detect additional site(s) of infection in patients with persistent or recurrent fever and a known infection site To survey for site(s) of abscess or infection in a febrile postoperative patient without localizing signs or symptoms. Fluid collections, ileus, bowel gas, fluid, and/or healing wounds reduce the specificity of computed tomography (CT) and ultrasound. To detect site(s) and extent of inflammatory bowel disease. 99mTc-labeled leukocytes may be preferable for this indication. To detect and follow up osteomyelitis primarily when there is increased bone remodeling secondary to joint prostheses, nonunited fractures, or sites of metallic hardware from prior bone surgery To detect osteomyelitis in diabetic patients when degenerative or traumatic changes, neuropathic osteoarthropathy, or prior osteomyelitis have caused increased bone remodeling To detect osteomyelitis involving the skull in postoperative patients and for follow-up of therapy To detect mycotic aneurysms, vascular graft infections, and shunt infections

44. Other diagnostic testing if focal neurological signs - CT head to rule out abscess, cancer if lethargy, confusion - LP to rule out meningoencephalitis, cancer if lymphadenopathy - HIV titer; lymph node biopsy to rule out lymphoma, cancer if cough, dyspnea - bronchoscopy, consider gastric aspirate for AFB, consider V/Q scan if hepatosplenomegaly or abdominal pain - CT abdomen if cardiac murmur - echocardiography if hepatic dysfunction - liver biopsy review of liver biopsy can be found in N Engl J Med 2001 Feb 15;344(7):495, commentary can be found in N Engl J Med 2001 Jun 28;344(26):2030

45. Other diagnostic testing II if headache, tenderness over temporal artery - temporal artery biopsy if bone pain - bone scan, metastatic bone series, protein immunoelectrophoresis if guaiac-positive stool - colonoscopy or barium enema and sigmoidoscopy if hematuria - renal ultrasound, IVP, cystoscopy bone marrow exam in suspected lymphoma, leukemia, miliary TB gallium scan and exploratory laparotomy rarely helpful

48. Prognosis over the last 10-15 years, new antibiotics and more sophisticated critical care have not changed high mortality rate of severe sepsis worsening neurologic, coagulation and renal dysfunction over first 3 days predicts increased mortality; prospective study of 287 patients with sepsis syndrome in intensive care units; pulmonary dysfunction was most common organ failure but not associated with 30-day mortality; other organ failures were less common at onset but significantly associated with 30-day mortality rate (Crit Care Med 2000 Oct;28(10):3405 in JAMA 2001 Jan 17;285(3):270)

49. Goal-directed therapy included central venous catheter that measured central venous oxygen saturation crystalloid 500 mg every 30 minutes as needed to maintain central venous pressure 8-12 mmHg vasopressors or vasodilators as needed to maintain mean arterial pressure 65-90 mmHg transfusion of red cells to hematocrit > 30% inotropic agents (dobutamine) as needed to maintain central venous oxygen saturation > 70%

50. Initial doses of IV antibiotics  ampicillin 100-150 mg/kg (50 mg/kg in neonates), maximum 4 g cefotaxime 50-75 mg/kg, maximum 3 g ceftriaxone 100 mg/kg, maximum 2 g ceftazidime 75 mg/kg (50 mg/kg in neonates), maximum 2 g chloramphenicol 25 mg/kg, maximum 1 g doxycycline (usually not recommended in children < 7) 2 mg/kg, maximum 100 mg gentamicin 2.5 mg/kg, maximum 100 mg (see also Single-daily dosing of aminoglycosides) penicillin G 50,000 units/kg, maximum 4 million U rifampin 20 mg/kg, maximum 600 mg vancomycin 15 mg/kg, maximum 500 mg

51. Corticosteroids  steroids may increase or decrease mortality depending on dosing; systematic review of 5 randomized trials of long-term (5-7 days) low-dose (mean total 1.2 g hydrocortisone equivalents) in sepsis or septic shock found improved survival and shock reversal; meta-analysis of 8 earlier randomized trials of short-term (1-2 days) high-dose (mean total 24 g hydrocortisone equivalents) steroids found increased mortality and vasopressor dependence (Ann Intern Med 2004 Jul 6;141(1):47 low-dose corticosteroids for at least 5 days may reduce mortality; systematic review of 15 trials of corticosteroids for severe sepsis or septic shock with 2,023 patients did not find significant reduction in overall 28-day mortality but conclusions limited by heterogeneity which appeared related to different dosing strategies; systematic review last updated 2003 Sep 19 (Cochrane Library 2004 Issue 1:CD002243), similar report can be found in BMJ 2004 Aug 28;329(7464):480,