Fever of Unknown OriginFever of Unknown Origin

Bryan YoureeBryan YoureeVanderbilt University Medical CenterVanderbilt University Medical Center

ObjectivesObjectives

Definition and pathophysiology of Definition and pathophysiology of feverfever

FUO: classifications and etiologyFUO: classifications and etiology

Diagnostic workup of FUODiagnostic workup of FUO

PrognosisPrognosis

Fever versus HyperthermiaFever versus Hyperthermia

FeverFever: resetting of the thermostatic set-: resetting of the thermostatic set-point in the anterior hypothalamus and the point in the anterior hypothalamus and the resultant initiation of heat-conserving resultant initiation of heat-conserving mechanisms until the internal temperature mechanisms until the internal temperature reaches the new level.reaches the new level.HyperthermiaHyperthermia: an elevation in body : an elevation in body temperature that occurs in the absence of temperature that occurs in the absence of resetting of the hypothalamic resetting of the hypothalamic thermoregulatory centerthermoregulatory center

Mechanisms of Hyperthermia and Mechanisms of Hyperthermia and Associated ConditionsAssociated Conditions

1. 1. Excessive heat productionExcessive heat production: exertional : exertional hyperthermia, thyrotoxicosis, hyperthermia, thyrotoxicosis, pheochromocytoma, cocaine, delerium pheochromocytoma, cocaine, delerium tremens, malignant hyperthermiatremens, malignant hyperthermia

2.2. Disorders of heat dissipationDisorders of heat dissipation: heat : heat stroke, autonomic dysfunctionstroke, autonomic dysfunction

3.3. Disorders of hypothalamic functionDisorders of hypothalamic function: : neuroleptic malignant syndrome, CVA, neuroleptic malignant syndrome, CVA, traumatrauma

What is the normal human body What is the normal human body temperature?temperature?

A.A. 37.537.5° C° C

B.B. 98.6° F98.6° F

C.C. 340.15 K340.15 K

D.D. Each human being is a unique individual, Each human being is a unique individual, and therefore, normal temperature and therefore, normal temperature cannot be defined.cannot be defined.

What is the normal human body What is the normal human body temperature?temperature?

A.A. 37.637.6° C° C

B.B. 98.6° F98.6° F

C.C. 340.15 K340.15 K

D.D. Each human being is a unique individual, Each human being is a unique individual, and therefore, normal temperature and therefore, normal temperature cannot be defined.cannot be defined.

Wunderlich’s MaximWunderlich’s Maxim

After analyzing >1 million axillary After analyzing >1 million axillary temperatures from temperatures from ~25,000 patients, ~25,000 patients, Wunderlich identified 37.0° C (36.2-37.5) Wunderlich identified 37.0° C (36.2-37.5) as the mean temperature in healthy adults.as the mean temperature in healthy adults.

Temperature readings >38.0° C were Temperature readings >38.0° C were deemed as “suspicious/probably febrile.”deemed as “suspicious/probably febrile.”

1Wunderlich C. Das Verhalten der Eiaenwarme in Krankenheiten. Leipzig, Germany: Otto Wigard;1868.2Mackowiak, et al., JAMA 1992;268:1578

Normal Body TemperatureNormal Body Temperature

For healthy individuals 18 to 40 years of age, For healthy individuals 18 to 40 years of age, the mean oral temperature is 36.8° ± 0.4°C the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F)(98.2° ± 0.7°F)Low levels occur at 6 A.M. and higher levels Low levels occur at 6 A.M. and higher levels at 4 to 6 P.M. at 4 to 6 P.M. The maximum normal oral temperature is The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.(99.9°F) at 4 P.M.These values define the These values define the 99th percentile99th percentile for for healthy individuals.healthy individuals.

Mackowiak, et al., JAMA 1992;268:1578

Normal Body Temperature CaveatsNormal Body Temperature Caveats

Rectal temperatures are generally 0.4°C Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. (0.7°F) higher than oral readings.

Tympanic membrane (TM) values are Tympanic membrane (TM) values are 0.8°C (1.6°F) lower than rectal 0.8°C (1.6°F) lower than rectal temperatures when thermometer is in the temperatures when thermometer is in the unadjusted-mode. unadjusted-mode.

How does fever occur?How does fever occur?

A.A. Build up of evil humorsBuild up of evil humors

B.B. IL-1 and IL-6IL-1 and IL-6

C.C. TNFTNF

D.D. Disruption of the medulla oblongataDisruption of the medulla oblongata

E.E. A and DA and D

F.F. B and CB and C

How does fever occur?How does fever occur?

A.A. Build up of evil humorsBuild up of evil humors

B.B. IL-1 and IL-6IL-1 and IL-6

C.C. TNFTNF

D.D. Disruption of the medulla oblongataDisruption of the medulla oblongata

E.E. A and DA and D

F.F. B and CB and C

Mackowiak, P. A. Arch Intern Med 1998;158:1870-1881.

Hypothetical Model for the Febrile Response

Interleukin-1 β and TNF-α play prominent rolesin fever production by stimulating the release ofcyclic AMP from the glial cells and activatingneuronal endings from the thermoregulatory center that extend into the area.

Bacterial PyrogensBacterial Pyrogens

Lipopolysaccharide (LPS) endotoxinLipopolysaccharide (LPS) endotoxinEndotoxin binds to LPS-binding protein and is transferred to CD14 Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNFon macrophages, which stimulates the release of TNFαα. .

Staphylococcus aureusStaphylococcus aureus enterotoxins enterotoxinsStaphylococcus aureusStaphylococcus aureus toxic shock syndrome toxic shock syndrome toxin (TSST)toxin (TSST)Both Both StaphylococcusStaphylococcus toxins are superantigens and activate T cells toxins are superantigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFleading to the release of interleukin (IL)-1, IL-2, TNFαα and TNF and TNFββ, , and interferon (IFN)-gamma in large amounts and interferon (IFN)-gamma in large amounts

Group A and B streptococcal toxins Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only Exotoxins induce human mononuclear cells to synthesize not only TNFTNFαα but also IL1 and IL-6 but also IL1 and IL-6

Fever of Unknown OriginFever of Unknown Origin(Historical Definition)(Historical Definition)

Fever of at least 3 weeks’ durationFever of at least 3 weeks’ duration

Temperature of 101Temperature of 101° F (38.3° C) on ° F (38.3° C) on several occasionsseveral occasions

No diagnosis after a 1 week No diagnosis after a 1 week evaluation in the hospitalevaluation in the hospital

Petersdorf and Beeson Medicine 1961;40:1

Historical Causes of FUOHistorical Causes of FUO

Hippocrates: excess of yellow bileHippocrates: excess of yellow bile

Middle Ages: demonic possession Middle Ages: demonic possession (encephalitis?)(encephalitis?)

1818thth Century: Friction associated with the Century: Friction associated with the flow of blood through the vascular system flow of blood through the vascular system and from fermentation and putrefaction and from fermentation and putrefaction occurring in the blood and intestinesoccurring in the blood and intestines

Categories of FUOCategories of FUOFeatureFeature NosocomialNosocomial NeutropenicNeutropenic HIV-associatedHIV-associated ClassicClassic

Patient’s Patient’s situationsituation

Hospitalized, Hospitalized, acute care, no acute care, no infection when infection when admittedadmitted

Neutrophil count Neutrophil count either <500/either <500/µL or µL or expected to reach expected to reach that level in 1-2 that level in 1-2 daysdays

Confirmed HIV-Confirmed HIV-positivepositive

All others with All others with fevers for fevers for ≥3 ≥3 weeksweeks

Duration of Duration of illness while illness while investigatedinvestigated

3 days3 daysbb 3 days3 daysbb 3 days3 daysbb (or 4 (or 4 weeks as weeks as outpatient)outpatient)

3 days3 daysbb or 3+ or 3+ outpatient outpatient visitsvisits

ExamplesExamples Septic Septic thrombophlebitis, thrombophlebitis, sinusitis, sinusitis, C. C. difficiledifficile colitis, colitis, drug feverdrug fever

Perianal infection, Perianal infection, aspergillosis, aspergillosis, candidemiacandidemia

MAIMAIcc infection, infection, TB, non-TB, non-Hodgkin’s Hodgkin’s lymphoma, drug lymphoma, drug feverfever

Infections, Infections, malignancy, malignancy, inflammatory inflammatory diseases, drug diseases, drug feverfever

aAll require temperatures of ≥38.3°C (101°F) on several occasions.bIncludes at least 2 days’ incubation of microbiology cultures.cM. avium/M. intracellulare.

Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds): Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

Etiology of FUO Over a 40 Year Etiology of FUO Over a 40 Year PeriodPeriod

Mourad, et al. Arch Intern Med. 2003;163:545

Infectious Causes of FUOInfectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc)Appendicitis, cholecystitis, tubo-ovarian abscess, pyometraIntracranial abscess, sinusitis, dental abscessChronic pharyngitis, tracheobronchitis, lung abscessSeptic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infectionWound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

Infectious Causes of FUOInfectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc)Appendicitis, cholecystitis, tubo-ovarian abscess, pyometraIntracranial abscess, sinusitis, dental abscessChronic pharyngitis, tracheobronchitis, lung abscessSeptic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infectionWound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

Infectious Causes of FUOInfectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc)Appendicitis, cholecystitis, tubo-ovarian abscess, pyometraIntracranial abscess, sinusitis, dental abscessChronic pharyngitis, tracheobronchitis, lung abscessSeptic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infectionWound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

Infectious Causes of FUOInfectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc)Appendicitis, cholecystitis, tubo-ovarian abscess, pyometraIntracranial abscess, sinusitis, dental abscessChronic pharyngitis, tracheobronchitis, lung abscessSeptic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infectionWound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

Infectious Causes of FUOInfectious Causes of FUO

Tuberculosis, Mycobacterium avium complex, syphilis, Q fever, legionellosisSalmonellosis (including typhoid fever), listeriosis, ehrlichiosis, Actinomycosis, nocardiosis, Whipple’s diseaseFungal (candidaemia, cryptococcosis, sporotrichosis, aspergillosis, mucormycosis, Malassezia furfur)Malaria, babesiosis, toxoplasmosis, schistosomiasis, fascioliasis, toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasisCytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus, parvovirus B19

Collagen Vascular DiseasesCollagen Vascular Diseases

Adult Still’s disease, SLEGiant cell arteritis/polymyalgia rheumatica, ankylosing spondylitisWegener’s granulomatosisRheumatic feverPolymyositis, rheumatoid arthritisFelty’s syndrome, eosinophilic fasciitis

MalignanciesMalignancies

LymphomaLymphoma

LymphomaLymphoma

LymphomaLymphoma

Renal cell carcinomaRenal cell carcinoma

Hepatocellular carcinomaHepatocellular carcinoma

Miscellaneous Causes of FUOMiscellaneous Causes of FUO

Complex partial status epilepticus, cerebrovascular accident, brain tumour, encephalitisDrug fever, Sweet’s syndrome, familial Mediterranean feverGout, pseudogoutKawasaki’s syndrome, Kikuchi’s syndromeCrohn’s disease, ulcerative colitis, sarcoidosis, granulomatous hepatitisDeep vein thrombosisDeep vein thrombosisAtelectasis?Atelectasis?

Drug FeverDrug FeverNo characteristic fever pattern No characteristic fever pattern was observed.was observed.Maximum temperatures Maximum temperatures ranged from 38ranged from 38°C to 43°C°C to 43°CThe mean lag time between The mean lag time between initiation of a drug and the initiation of a drug and the onset of fever was 21 days, onset of fever was 21 days, but lag times varied but lag times varied considerably.considerably.Alpha methyldopa and Alpha methyldopa and quinidine were the two drugs quinidine were the two drugs most commonly implicated, most commonly implicated, but antimicrobials (as a group) but antimicrobials (as a group) were responsible for the were responsible for the largest number of episodes.largest number of episodes.

Episodes Episodes in Dallas in Dallas (n=51)(n=51)

Episodes Episodes in Lit. in Lit. (n=97)(n=97)

Total Total Episodes Episodes (n=148)(n=148)

nn nn %%

Gender (male/female)Gender (male/female) 27/1827/18 53/4453/44 56/4456/44

Hx of atopic diseaseHx of atopic disease 00 33 22

Previous hx of drug allergyPrevious hx of drug allergy 44 1212 1111

Fever patterns reportedFever patterns reported

ContinuousContinuous

RemittentRemittent

IntermittentIntermittent

HecticHectic

5151

00

1919

66

2626

4141

99

77

1313

1212

6262

1010

2828

2121

4141

RigorsRigors 2626 5252 5353

Relative bradycardiaRelative bradycardia 55 44 1111

HypotensionHypotension 66 2121 1818

RashRash

PruritusPruritus

2020

1111

66

00

1818

77

Leukocytosis (>10K)Leukocytosis (>10K) 1111 00 77

Eosinophilia (>300/mmEosinophilia (>300/mm33)) 2121 1212 2222

HematologicHematologic 11 1212 99

DeathsDeaths 22 44 44

Mackowiak and LeMaistre Ann Intern Med 1987;106:728

Minimal Initial Diagnostic Workup Minimal Initial Diagnostic Workup For FUOFor FUO

Comprehensive historyComprehensive historyPhysical examinationPhysical examinationCBC + differentialCBC + differentialBlood film reviewed by hematopathologistBlood film reviewed by hematopathologistRoutine blood chemistryRoutine blood chemistryUA and microscopyUA and microscopyBlood (x 3) and urine culturesBlood (x 3) and urine culturesAntinuclear antibodies, rheumatoid factorAntinuclear antibodies, rheumatoid factorHIV antibodyHIV antibodyCMV IgM antibodies; heterophile antibody test (if c/w mono-like CMV IgM antibodies; heterophile antibody test (if c/w mono-like syndrome)syndrome)Q-fever serology (if risk factors)Q-fever serology (if risk factors)Chest radiographyChest radiographyHepatitis serology (if abnormal LFTs)Hepatitis serology (if abnormal LFTs)

Mourad, et al. Arch Intern Med. 2003;163:545

Liver Biopsy and Bone Marrow Liver Biopsy and Bone Marrow BiopsyBiopsy

Diagnostic yield of liver Diagnostic yield of liver biopsy has ranged from biopsy has ranged from 14% to 17%.14% to 17%.

Physical exam finding of Physical exam finding of hepatomegaly or hepatomegaly or abnormal liver profile are abnormal liver profile are not helpful in predicting not helpful in predicting abnormal biopsy result.abnormal biopsy result.

Complication rate is Complication rate is 0.06% to 0.32%0.06% to 0.32%

The diagnostic yield of bone marrow cultures in immunocompetent individuals has been found to be 0% to 2%1,2

Mourand et al. Arch Intern Med 2003;163:545

1Volk et al. J Clin Pathol 1998;110:150 2Riley et al. J Clin Pathol 1995:48:706

Diagnostic Value of NaproxenDiagnostic Value of Naproxen

77 patients presenting 77 patients presenting with FUO were treated with FUO were treated with naproxen.with naproxen.Overall temperature Overall temperature decreased from decreased from 39.139.1°C to 37.4°C.°C to 37.4°C.The sensitivity of the The sensitivity of the naproxen test for naproxen test for neoplastive fever was neoplastive fever was 55% and the 55% and the specificity was 62%.specificity was 62%.

Vanderschueren, et al. Am J Med 2003;115:572

Copyright restrictions may apply.

Mourad, O. et al. Arch Intern Med 2003;163:545-551.

Proposed Approach to FUO

Mourad, et al. Arch Intern Med. 2003;163:545

Marik, P. E. Chest 2000;117:855-869

Approach to Fever in the ICU

PrognosisPrognosis

Prognosis is determined primarily by the Prognosis is determined primarily by the underlying disease.underlying disease.

Outcome is worst for neoplasms.Outcome is worst for neoplasms.

FUO patients who remain undiagnosed FUO patients who remain undiagnosed after extensive evaluation generally have a after extensive evaluation generally have a favorable outcome and the fever usually favorable outcome and the fever usually resolves after 4-5 weeks.resolves after 4-5 weeks.

Larson et al. Medicine 1982;61:269

SummarySummary

FUO is often a diagnostic dilemmaFUO is often a diagnostic dilemma

Infections comprise Infections comprise ~30% of cases~30% of cases

Bone marrow biopsies are of low Bone marrow biopsies are of low diagnostic yielddiagnostic yield

Diagnostic approach should occur in a Diagnostic approach should occur in a step-wise fashion based on the H&Pstep-wise fashion based on the H&P

Patient’s that remain undiagnosed Patient’s that remain undiagnosed generally have a good prognosisgenerally have a good prognosis