Fever of Unknown Origin

Chutchawan Ungthammakhun, M.D.

Infectious Disease Division, Department of Internal medicine
Phramongkutklao Hospital and College of Medicine
 Classification of FUO
Nosocomial (health care associated)
 Definition : condition in which patients first manifest fever during active medical
treatment for other illness (hospitalized patients)
 Risk factors : surgical procedures, urinary and respiratory tract instrumentation,
intravascular devices, treatment (drugs and blood transfusion), immobilization

“Fever of too many origins”

Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci 2012;344:307–16
Durack DT, Street AC. Fever of unknown origin reexamined and redefined. Curr Clin Top Infect Dis 1991;11:35–51
Konecny P, Davidson RN. Pyrexia of unknown origin in the 1990s: time to redefine. Br J Hosp Med 1996;56: 21–4
 Nosocomial (health care associated)
Postoperative Patients
 Response to surgically induced tissue injury with release of pyrogenic cytokines
and interleukins rather than result of infection
 Incidence in patients undergoing major gynecologic surgery are 211/537 (39%)
 Median length of infectious cause in postoperative fever :
 Urinary tract infections : 2 days (range: 1–7 days)
 Pneumonia : 3 days (range: 2–4 days)
 Postoperative fevers generally do not require extensive diagnostic investigation

Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever: where is the clinical evidence? Chest 2011;140:418-24
Neuhoff FJ, Brewer JE, Castaneda T, et al. Frequency and yield of postoperative fever evaluation. Infect Dis Obstet Gynecol 1998;6:252–5
Kendrick JE, Numnum TM, Estes JM, et al. Conservative management of postoperative fever in gynecologic patients undergoing major abdominal or vaginal operations. J Am Coll Surg 2008;207:393–7
Shaw JA, Chung R. Febrile response after knee and hip arthroplasty. Clin Orthop Relat Res 1999;367:181–9
 Nosocomial (health care associated)
Intensive Care Units (ICU) Patients
 Fever is common (70%) and developing early after admission (within first 1–2 days)
 The complexity of patients in ICUs
 Cause multiple processes may be occurring simultaneously
 Infected with multiple organisms, several site of infection
 Prognosis in nosocomial fever in ICU patients (mortality rate)
 Noninfectious origins : febrile (37%) VS afebrile (27 %); (p = 0.38)
 Duration of fever : >5 days (62.5% ) VS ≤5 days (29.6%); (p < 0.0001)
 Etiologies are not different from general causes of health care–associated fevers
Circiumaru B, Baldock G, Cohen J. A prospective study of fever in the intensive care unit. Intensive Care Med 1999;25:668–73
van Zanten AR, Dixon JM, Nipshagen MD, et al. Hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients. Crit Care 2005;9:R583-R90
Seguin P, Roquilly A, Mimoz O, et al. Risk factors and outcomes for prolonged versus brief fever: a prospective cohort study. Crit Care 2012;16(4):R150
 Nosocomial (health care associated)
Stroke Patients
 Fever is usually the result of infection (documented infection 22.7%)
 Urinary tract infection : 11.5% (related to urinary catheterization)
 Respiratory tract infection : 10%
 Other : 1.2%
 Stroke itself may not respond to empirical antibiotic therapy and associated with
 Intracerebral hemorrhage with mass effects  Transtentorial herniation
 Large size of ischemic infarct or hemorrhage  Intraventricular bleeding
 Fever in stroke patients tended to occur earlier after onset of stroke

Georgilis K, Plomaritoglou A, Dafni U, et al. Aetiology of fever in patients with acute stroke. J Intern Med 1999;246:203–9
 Nosocomial (health care associated)
Drug associated fever
 Frequently overlooked because of lack of localizing signs and inappropriately well
 Clinical presentation : eosinophilia (25%), relative bradycardia (10%), rash (5%)
 May occur at any point during course of drug therapy
 Anti-neoplastic agents (median 0.5 days, mean 6 days) : may higher temperature than other agents

 Antimicrobials agents (median 6 days, mean 7.8 days) : fever disappearing within 72 hours after stop
 Central nervous system agents (median 16 days, mean 18.5 days) : serotonin syndrome, NMS
 Cardiovascular agents (median 10 days, mean 44.7 days)

 Degree of pyrexia can vary ranging from 37.2 to 42.8°C (the most common : 38.9 – 40 °C)

HarrisLF, HoldsambeckHK. Drug fever : surprisinglycommonand costly.Ala Med 1986;56:19–22

Johnson DH, Cunha BA. Drug fever. Infect Dis Clin NorthAm1996;10:85–91
Tabor PA. Drug-induced fever. Drug Intell Clin Pharm1986;20:413–20
Tisdale JE, Miller DA. Drug-induced diseases:prevention, detection, and management. Bethesda,MD: American Society of Health-SystemsPharmacists,2005
 Nosocomial Fever
Infectious cause

Occult infection with reactivation Devices associated infection Abnormal Host factors

Vascular catheter
HIV, Herpes virus Foley’s ETT with Draining Neurogenic Prolong
Tuberculosis Melioidosis NG tube (C-line, A-line, PICC Bed ridden
infection (HSV, HZV) catheter ventilator catheter bladder/BPH antibiotics
line, DLC)

Wound/drainage Pressure sore,

CRBSI, dialysis aspiration C. difficile
Sinusitis CA-UTI VAP catheter associated UTI
related infection pneumonia, infection
infection
acalculous
cholecystitis

Noninfectious cause

Treatment related Disease related Other diagnosis

Neoplastic fever Huge hematoma

Side effects Post Central fever Adrenal Thrombosis Arthritis
Drug fever (HCC, RCC, colon, (infected/non Atelectasis Phlebitis
of drugs procedure (intracranial lesion) insufficiency (DVT, PE) (gout, CPPD)
hematologic) infected)
 Evaluation of Patients with FUO

 Comprehensive history
 Verification that the patient
actually has fever
 Consideration of the fever pattern

 Repeated physical examinations

 Investigations : laboratory, key

imaging studies, invasive diagnostic
procedures
Mandell, Douglas, and Bennett’s, Principles and practice of Infectious disease, Ed 9 th
de Kleijn EM, Vandenbroucke JP, van der Meer JW. Fever of unknown origin (FUO). I. a prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. Medicine (Baltimore) 1997;76:392-400
Wright WF, Auwaerter PG. Fever and fever of unknown origin: review, recent advances, and lingering dogma. Open Forum Infect Dis 2020;7(5):ofaa132
 Diagnosis of FUO
History Taking Should be Attention
 Recent travel, work environment
 Exposure to pets and other animals
 Recent contact with people exhibiting similar
symptoms
 Past medical history (lymphoma, rheumatic fever,
intraabdominal disorders : complications or
reactivation)
 List of the patient’s medications may be evaluated as
drug-induced fever

Mandell, Douglas, and Bennett’s, Principles and practice of Infectious disease, Ed 9th
 Diagnosis of FUO
History Taking
 Night sweats are nonspecific but may be
associated : tuberculosis, autoimmune,
hematologic malignancy

 Documented weight loss : malignancy,

tuberculosis, HIV infection, endocrine
disorders

 History of calf swelling, pain, redness :

suggestive of deep venous thrombosis
Mandell, Douglas, and Bennett’s, Principles and practice of Infectious disease, Ed 9th
 History Taking
Verification of Fever and Fever Pattern
 Importance of this step should
be self-evident that often
overlooked
 National Institutes of Health for
Malaria Typhoid fever
investigation of prolonged fever (Pv/Po : 48 hr., Pm : 72 hr. , Pf) (relative bradycardia : Faget sign)
35% were determined no
significant fever at all
 Fever pattern are rarely use for
diagnostic, they occasionally
offer useful information Hodgkin disease Borreliosis
(Pel-Ebstein pattern) (relapsing fever pattern)
Aduan RP, Fauci AS, Dale DC, et al. Prolonged fever of unknown origin (FUO): a prospective study of 347 patients. Clin Res 1978;26:558A
Woodward TE. The fever pattern as a clinical diagnostic aid. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. 2nd ed. Philadelphia: Lippincott-Raven; 1997:215–35
Mandell, Douglas, and Bennett’s, Principles and practice of Infectious disease, Ed 9th
 History Taking
Verification of Fever and Fever Pattern
 Resolution of fever after disease-specific therapy
(such as empirical therapy for suspected
tuberculosis) may provide evidence to support
presumptive diagnosis

 Relationship between high fever

and likelihood of bacteremia in adults
 Commonly believed that there may be relationship
 Belief has not been proved *

Woodward TE. The fever pattern as a clinical diagnostic aid. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. 2nd ed. Philadelphia: Lippincott-Raven; 1997:215–35
McCarthy PL, Dolan TF. Hyperpyrexia in children. Am J Dis Child 1976;130:849–51
McCarthy PL, Jekel JF, Dolan TF. Temperature greater than or equal to 40°C in children less than 24 months of age: a prospective study. Pediatrics 1977;59:663–8
 History Taking
Verification of Fever and Fever Pattern
Height of fever correlates roughly with likelihood of bacteremia in pediatric populations
30 26
Incidence of bacteremia

25
20
15 13
(%)

10 7
5
0
< 40°C 40.5 to 41°C >41°C
Degree of fever (oC)
In children with bacteremia in which there is little or no fever
Nonbacteremic conditions (drug-induced fever, thrombophlebitis, pulmonary emboli) sometimes are extremely high fevers
McCarthy PL, Dolan TF. Hyperpyrexia in children. Am J Dis Child 1976;130:849–51
McCarthy PL, Jekel JF, Dolan TF. Temperature greater than or equal to 40°C in children less than 24 months of age: a prospective study. Pediatrics 1977;59:663–8
 Diagnosis of FUO
Physical Examination
Site Finding Diagnosis
 Abnormal physical findings Head Sinus tenderness Sinusitis
were reported to diagnosis in Temporal artery Nodules, reduced pulsations Temporal arteritis
Oropharynx Ulceration, toothache, oral ulcer Disseminated histoplasmosis,
60% of FUO periapical abscess
Fundi or Choroid tubercle, petechiae, Roth Disseminated TB/histoplasmosis,
 Key physical abnormalities are conjunctivae spot endocarditis
so subtle as to require repeated Thyroid Enlargement, tenderness Thyroiditis

examinations (abnormalities were Heart Murmur (new) Infective or marantic endocarditis

Abdomen Enlarged iliac crest lymph nodes, Lymphoma, endocarditis,
detected only after repeated splenomegaly, hepatosplenomegaly disseminated TB/histoplasmosis
examinations) Rectum Perirectal fluctuance/tenderness, Abscess
Prostatic tenderness/fluctuance
Genitalia Testicular nodule, Epididymal Periarteritis nodosa
nodule
Lower extremities Deep venous tenderness Thrombosis or thrombophlebitis
Skin and nails Petechiae, splinter hemorrhages, Vasculitis, endocarditis
subcutaneous nodules, clubbing
Pizzo PA, Lovejoy FH, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics 1975;55:468–73
Lohr JA, Hendley JO. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. Clin Pediatr. 1977;16:768–73
 Diagnosis of FUO
Laboratory Investigations

 Should be selectively applied using diagnostic clues from history and physical
examination to direct choice and sequence of tests

 Inappropriate diagnostic tests evaluation may delay identification of correct

diagnosis and misguided treatment plans due to false-positive tests

 Useful tests for diagnosis : serologic tests for pathogens (procalcitonin level for
bacterial pneumonia, beta-D-glucan for candida or mold) and rheumatologic disorders

Giacobbe DR, Mikulska M, Tumbarello M, et al. Combined use of serum (1,3)-β-Dglucan and procalcitonin for the early differential diagnosis between candidaemia and bacteraemia in intensive care units. Crit Care 2017;21:176
Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci 2012;344:307–16
de Kleijn EM, van Lier HJ, van der Meer JW. Fever of unknown origin (FUO), II. Diagnostic procedures in prospective multicenter study of 167 patients. The Netherlands FUO study group. Medicine (Baltimore). 1997;76:401–14
Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: a clinical approach. Am J Med 2015;128:1138. e1–1138.e15
Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86:26–38
 Diagnosis of FUO
Laboratory Investigations : Basics

 Complete blood count with differential

 BUN/creatinine
 Liver function tests
 Erythrocyte sedimentation rate
 Urine and blood cultures
 Chest radiography

Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci 2012;344:307–16
 Diagnosis of FUO
Laboratory Investigations : Advance
 Bone marrow examination should be considered for
 Diagnosis of suspected granulomatous diseases
(tuberculosis, histoplasmosis, sarcoidosis),
carcinomatosis, hemophagocytic syndrome
 Especially in patients with abnormal complete
blood cell counts
 Procalcitonin levels may be of use in differentiating
infection (elevated levels) from acute organ
rejection in transplant patients
Hot A, Jaisson I, Girard C, et al. Yield of bone marrow examination in diagnosing the source of fever of unknown origin. Arch Intern Med 2009;196:2018–23
Pande A, Bhattacharyya M, Pain S, et al. Diagnostic yield of bone marrow examination in HIV associated FUO in ART naïve patients. J Infect Public Health. 2010;3:124–9
Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis 2003;36:306–12
Kuse ER, Langefeld I, Jaeger K, et al. Procalcitonin in fever of unknown origin after liver transplantation: a variable to differentiate acute rejection from infection. Crit Care Med 2000;28:555–9
 Diagnosis of FUO
Imaging Studies
 Computed tomography of abdomen, ultrasound imaging of gallbladder and
hepatobiliary system have been used extensively to evaluate cases of FUO

 Diagnostic utility of imaging techniques in patients with FUO

 Plain-film chest radiography : 60%
 Chest CT : 82%
 Abdominal ultrasound : 86%
 Abdominal CT : 92%

Knockaert DC, Vanneste LJ, Vanneste SB, et al. Fever of unknown origin in the 1980s: an update of the diagnostic spectrum. Arch Intern Med 1992;152:51–5
Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86:26–38
 Diagnosis of FUO
Imaging Studies
 Labeled autologous leukocytes (Indium 111-tagged WBC scan)
 Used for evaluating FUO in the past, but now fallen out due to low sensitivity
 Some report showed higher diagnostic yield than CT or ultrasound scanning

 67Ga scan (radioactive tracer)

 Particularly effective in visualizing chronic infections and lymphomas
 Disadvantages : causing largely displaced by CT and MRI
 24 to 72-hour delay period between injection and imaging
 Relatively high radiation dose but suboptimal image quality

Knockaert DC, Mortelmans LA, De Roo MC, et al. Clinical value of gallium-67 scintigraphy in evaluation of fever of unknown origin. Clin Infect Dis 1994;18:601–5
Syrjala MT, Valtonen V, Liewendahl K, et al. Diagnostic significance of indium-111 granulocyte scintigraphy in febrile patients. J Nucl Med 1987;28:155–60
 Diagnosis of FUO
Imaging Studies
 Magnetic Resonance Imaging (MRI)

 Most common diseases diagnosed were

giant cell arteritis (55%), Takayasu arteritis
(27%), Wegener granulomatosis (9%),
microscopic polyangiitis (9%)
 Diffusion-weighted MRI : especially useful
for evaluation of central nervous system ,
abdomen, spleen and lymph nodes

Knockaert DC, Vanneste LJ, Vanneste SB, et al. Fever of unknown origin in the 1980s: an update of the diagnostic spectrum. Arch Intern Med 1992;152:51–5
Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86:26–38
 Diagnosis of FUO
Imaging Studies
 18F-fluorodeoxyglucose–positron
emission tomography (FDG-PET)
 FDG uptake is related to increased
cellular glucose metabolism
Should be considered when conventional diagnostic methods have been
 Present in numerous hypermetabolic
unsuccessful in the diagnosis of an etiology for FUO : useful for localizing lesions
conditions : tumors, focal areas of
infection > noninfectious inflammatory
conditions
Overall pooled for diagnosis FUO
sensitivity of 98.2% and specificity of 85.9%

Negative test results associated with high likelihood of spontaneous remission of fever
Blockmans D, Knockaert D, Maes A, et al. Clinical value of [18F] fluoro-deoxyglucose positron emission tomography for patients with fever of unknown origin. Clin Infect Dis 2001;32:191–6
Dong MJ, Zhao K, Liu ZF, et al. A meta-analysis of the value of fluorodeoxyglucose-PET/PET-CT in the evaluation of fever of unknown origin. Eur J Radiol 2011;80:834–44
Takeuchi M, Dahabreh IJ, Nihashi T, Iwata M, Varghese GM, Terasawa T. Nuclear imaging for classic fever of unknown origin: meta-analysis. J Nucl Med 2016;57:1913-9
 Diagnosis of FUO
Invasive Diagnostic Procedures
 Histopathologic examination of tissues provide definitive diagnosis in some cases
 Specific etiologies based on clinical features and noninvasive tests : 61%
 Invasive procedures were performed in 79%, diagnostic benefit was obtained only 49%
 Most helpful in patients with solid cancers, lymphomas, disseminated tuberculosis
 The diagnostic yield of operative and CT-guided biopsies is higher than bedside
biopsy procedures
 The exception of blind biopsies of temporal artery (in elderly FUO) with ESR
greater than 50 to 100 mm/h (even in absence of localizing signs) may be used
Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993;41:1187–92
Kazanjian PH. Fever of unknown origin: review of 86 patients treated in community hospitals. Clin Infect Dis 1992;15:968–73
Mansueto P, Di Lorenzo G, Rizzo M, et al. Fever of unknown origin in a mediterranean survey from a division of internal medicine: report of 91 cases during a 12-year-period (1991–2002). Intern Emerg Med 2008;3:219–25
Mete B, Vanli E, Yemisen M, et al. The role of invasive and non-invasive procedures in diagnosing fever of unknown origin. Int J Med Sci 2012; 9: 682–9
Ozaras R, Celik AD, Zengin K, et al. Is laparotomy necessary in the diagnosis of fever of unknown origin? Acta Chir Belg 2005;105:89–92
 Management
Therapeutic Trials
 Empirical therapy with anti-inflammatory (steroids, aspirin, NSAIDs), antimicrobial
agents, was often given with intent of providing indirect diagnostic test in FUO
 Empirical therapeutic trials should be reserved for those very few patients
 Successful in reducing fever but may delay
correct diagnosis and appropriate treatment of FUO
 In whom all other approaches have failed
 Seriously ill (neutropenia, severely immunocompromised, rapidly deteriorating
clinical status) that therapy cannot be withheld for further period of observation

Durack DT. Fever of unknown origin. In: Mackowiak PA, ed. Fever. Basic Mechanisms and Management. 2nd ed. Philadelphia: Lippincott-Raven; 1997:237–49
Chang JC, Hawley BH. Neutropenic fever of undetermined origin (N-FUO): why not use the naproxen test? Cancer Invest 1995;13:448–50
Rolston KVI. Neoplastic fever: all who shiver are not infected. Support Care Cancer 2005;13:870–7
Knockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow-up of patients with undiagnosed fever of unknown origin. Arch Intern Med 1996;156:618-20
 Management
Therapeutic Trials
 Fevers caused by malignant neoplasms have been reported to respond better to
NSAIDs (naproxen) than fevers of infectious origin (but remains unvalidated)
 Therapeutic trials with limited spectrums of activity (antimycobacterial) continue
to be acceptable when other methods have failed
 The limitations and risks of empirical therapeutic trials are obvious
 Rifampin : highly active against bacterial species other than
Mycobacterium tuberculosis
 Fluoroquinolones : beneficial effect on tuberculosis or Q fever

Durack DT. Fever of unknown origin. In: Mackowiak PA, ed. Fever. Basic Mechanisms and Management. 2nd ed. Philadelphia: Lippincott-Raven; 1997:237–49
Chang JC, Hawley BH. Neutropenic fever of undetermined origin (N-FUO): why not use the naproxen test? Cancer Invest 1995;13:448–50
Rolston KVI. Neoplastic fever: all who shiver are not infected. Support Care Cancer 2005;13:870–7
 Management
Therapeutic Trials
 Therapeutic antimicrobial trials

 Predisposition to resistance or
suppress growth of fastidious
pathogens

 In case of self-limited conditions

(viruses) may result in false
reassurance that underlying
cause of fever has been treated
Haidar G, Singh N. Fever of unknown origin. New England Journal of Medicine. 2022 Feb 3;386(5):463-77
 Management

 Few formal guidelines, decisions FUO management have certainly more complex
 Principle in management of classic FUO :
 Therapy should be withheld until the cause of the fever has been determined
 Treatment can be tailored to specific diagnosis
 Important exception for empirical treatment with
 Corticosteroids may be appropriate in patients with suspected temporal arteritis to
prevent vascular complications
 Febrile neutropenic should generally receive broad-spectrum antimicrobial therapy
immediately after samples for appropriate cultures have been obtained

Durack DT. Fever of unknown origin. In: Mackowiak PA, ed. Fever. Basic Mechanisms and Management. 2nd ed. Philadelphia: Lippincott-Raven; 1997:237–49
Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56-e93
 Conclusion

 Initial evaluation reveals diagnostic clues that strongly support certain diagnosis

 High quality diagnostic workup after reasonable amount of time (rule out self-
limited fevers)
 Advances molecular diagnostics (DNA or RNA sequencing), PET/CT
 Available only in high-income settings
 Developing countries need access to rapid and reliable point-of-care testing

 Clinical judgment should be used in deciding whether to pursue therapeutic

challenges