This document discusses fever of unknown origin (FUO). It begins by classifying FUO into categories like classical FUO and nosocomial FUO. It then discusses the epidemiology and common etiologies of FUO, which include infections, collagen vascular diseases, and malignancies. The diagnostic approach involves a thorough history, repeated physical exams, and diagnostic testing like blood tests, imaging, and biopsies. Empirical therapeutic drug trials can help diagnose certain conditions but have limitations. The prognosis depends on the underlying cause, with poorer outcomes seen in elderly patients or those with neoplasms or diagnostic delays.
9. Epidemiology and Etiology
Infections 30 - 60 %
Collagen Vascular Disease 20 – 35 %
Malignancies 10 – 20 %
Miscellaneous 15 – 20 %
Undiagnosed 10 – 15 %
Categories of PUO in India
Handa et al
Handa et al
(1996)
D Kejarwal et
al (2001)
Di panjan
Bhandyopadha
yay et al (2011)
Infections 43.8% 53% 53.8%
Collagen Vascular
Disease
15.7% 11% 11%
Neoplasm 8.3% 17% 22%
10. Etiologies of FUO
Infection: Three major causes
Intracellular organisms. (Salmonella
Mycobacterium, Brucella)
Intravascular … SBE
Abscess .. especially occult ..
11. Etiologies of FUO
Infection- Tuberculosis: .. Disseminated
Single most common infection in most PUO series
Usually extrapulmonary or miliary, or
Occurs in the lungs and significant pre-existing lung
disease.
Pulmonary TB in HIV is often subtle (normal chest x-
rays 15 – 30%).→
PPD is (+ve) < 50% of TB with FUO.
Diagnosis often requires Bx of LN/Liver/Bone
marrow.
Sputum smear (+) only15- 25%
12. Etiologies of FUO
Bacterial Endocarditis:
Culture remains negative in 5-30% of patient.
Culture negative is likely with the following organisms:
Coxiella burnetii no growth.→
HACEK group incubate blood 7 – 21 days→
Brucella } Special media/
Legionelle } long time
Mycoplasma/Chlamydia }
Fungal usually sterile→
Peripheral signs may not be detected.
Right-side Endocarditis Lack murmurs self antibiotics→ → →
growth (-ve).
13. Etiologies of FUO
Abscess:
Usually located in abdomen or pelvis.
Secondary to appendicitis or diverticulitis.
Pyogenic liver abscess usually follow biliary tract dis./abd.
Suppuration.
Splenic abscess is usually secondary to hematogenous
seeding.
Perinephric or renal abscess is usually secondary to UTI.
Subphrenic Abscess
Retroperitoneal Abscess
Paravertebral Abscess
14. Etiologies of FUO
Collagen-Vascular-Disease
You need to recognize the syndrome otherwise no
diagnosis
SLE
Still’s disease (young or adult)—23-50%
Giant cell arteritis } 15% of PUO→
Polymyalgia Rheumatica }
Behcet’s Disease
Relapsing polychondritis
15. Etiologies of FUO
Malignancy
Lymphoma … Fever is a presenting feature
Leukemia … M. Myeloma
Renal cell carcinoma …
HCC or secondary metastasis to the liver
Benign Neoplasm
16. Etiologies of FUO
Miscellaneous Causes: (Non-Infectious)
Vascular Causes:
Pulmonary Emboli
50% are febrile
Fever is < 39o
C
Patient typically has predisposing factors cancer or recent→
immobility.
Hematoma in closed space
When it cause PUO usually arise from hemorrhage in the→
retroperitoneal space or within the wall of an aneurysm or
dissection of the thoracic or abdominal aorta.
17. Etiologies of FUO
Hyperthyroidism
Occasionally cause PUO most frequently diagnosed clinically.→
Often accompanied by weight loss.
Familial Mediterranean Fever
Recurrent fever
Arthritis pain out of proportional to signs
Polyserositis (peritonitis … may be pleuritis)
Leukocytosis
Not always hereditary
18. Etiologies of PUO
Factitious Fever
Febrile PUO
In one study … 9% of cases of PUO
False fever: thermometer manipulation using external
heat or substitute thermometer.
H/O Psychiatric illness
Increasing somewhat in elderly …
Generally young women with connection to health care
… often NURSES.
21. Drug Fever
No characteristic fever pattern
was observed.
Maximum temperatures
ranged from 38°C to 43°C
The mean lag time between
initiation of a drug and the
onset of fever was 21 days, but
lag times varied considerably.
Alpha methyldopa and
quinidine were the two drugs
most commonly implicated,
but antimicrobials (as a
group) were responsible for
the largest number of
episodes.
EpisodesEpisodes
in Dallasin Dallas
(n=51)(n=51)
EpisodesEpisodes
in Lit.in Lit.
(n=97)(n=97)
TotalTotal
EpisodesEpisodes
(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 1997;106:728
23. History
Verify the presence of fever:
Duration & Pattern of Fever
Tertian & Quartian Pattern→ Malaria
Pel-Ebstein Pattern → Lymphoma
Pulse-Temp Dissociation → Typhoid/Brucellosis
24. History
Family History:
Scrutinized for possible infectious or hereditary
disorders
Tuberculosis
FMF
Past Medical Condition:
Lymphoma,Rheumatic Fever,Still’s Disease,Behcet’s
Disease may recur→
Travel History
Work Environment
Exposure to sexual partner … HIV, Syphilis
Illicit drug abuse (IV) … Infective endocarditis,
Hepatitis … HIV
27. Physical Examination
Examine the Skin:
Rash:
SLE ….. All types of rashes is described
Still’s Disease Evanescent erythematous rash over the trunk
Infective Endocarditis (Janeway’s lesion)
Typhoid Fever … rose spots over abdomen
Osler’s Nodes: Painful nodule on the pads of toes & fingers →
Infective Endocarditis
28. Physical Examination
Examine for Oral Ulcer
SLE
Behcet’s Syndrome
Examine for Arthritis
Examine the Fundus
Roth’s spots (white-centered haemorrhage) Infective→
Endocarditis
Yellowish-white choroidal lesion Tuberculosis→
Choriodoretinitis Active Toxo or CMV in HIV patient.→
31. Diagnostic Testing
ESR
If elevated significant inflammatory process→
Greatest use in establishing a serious underlying disease,
esp. if v. high ESR > 100 mm/h …→
Tuberculosis,Myeloma,Temporal arteritis
CRP-closely associated with inflammatory process
• ESR & CRP is elevated in:
• 1.Bacterial Infection 2. Neoplasm
3.Immunological-mediated inflammatory states
4.Tissue infarction
33. Diagnostic Testing- Second Evaluation
Blood Testing
Anti-nuclear Antibodies
Rheumatoid Factor
CMV & EBV Antibody … IgM
Brucellosis AB titre
Thyroid Function Test
HIV Screening
34. Diagnostic Testing- Second Evaluation
CT-Scan CT scan chest→
Mediastinal mass Tuberculosis/Lymphoma/ Sarcoidosis→
Dorsal Spine Spondylitis and disc space disease→
CT-Scan Abdomen very effective to visualize→
All types of abscesses
Retroperitoneal tumor, lymph node or haematoma
ECHO
Bone Marrow Aspiration & Culture
Colonoscopy & Biopsy
Radionucletide scans
PET scan
35. Therapeutic Trials
Limitations and risk of empirical therapeutic trials:
Rarely specific
Underlying disease may remit spontaneously false
impression of success.
Disease may respond partially and this may lead to delay in
specific diagnosis.
Side effect of the drugs can be misleading.
36. Therapeutic Trials
Antimicrobial Trials:
Expected to suppress, but not cure, an infectious process
such as abscess may have false feeling of response.→
Failure to have quick response does not mean wrong→
diagnosis:
Endocarditis
Pelvic inflam. Disease
Typhoid Fever
Start early in certain conditions- Cirrhosis , Asplenia ,
Biologic Therapy, on Immuno Suppressive,Travel
Exposure
38. Therapeutic Trials
Empiric drug trial for suspected T.B:
Presence of granuloma on Bx before culture result.
Elderly or immunocompromised patient with (+ve) TB skin
test and deteriorating clinical condition.
No drug for stable patient without any suggestive features
laboratory result.
39. Therapeutic Trials
Empiric drug trial for suspected culture:
(-ve) Endocarditis:
Patient with new or changing murmur or peripheral signs of
endocarditis.
40. Therapeutic Trials
Empiric drug trials for suspected Vasculitis:
Elderly with weight loss and any symptoms suggestive
(headache, visual disturbance, jaw claudication) and ESR >↑
50 mm/hr →
Patient above 50 yrs who is c/o muscle pain and stiffness
around hip and shoulder with ESR↑ →
Ongoing vasculitis
Dramatic response is enough to establish the DX.
NSAIDS & Colchichine
41. Prognosis
It depends on:
Cause of fever
Nature of the underlying disease(s) BUT .. Generally
poor in:
Elderly
Neoplasm
Diagnostic delay has adverse effect in:
Intra Abdominal Infection
Miliary Tuberculosis
Recurrent Pulmonary Emboli
Disseminated Fungal Infection
Temporal Arteritis
42. Outcome
If the cause of fever remains elusive repeat history→
and examination.
5 – 15% of cases The diagnosis remain obscure.→
However, most of these patients defervesce without
treatment no disease later.→
57. Etiologies of PUO
Alcoholic Hepatitis
Often unsuspected pt. deny→
Fever is usually low grade < 38.5o
C
May have jaundice and hepatomegaly.
AST > ALT 2:1 AST < 500↑
Leukocytosis is often there.
If you do not think about it in the right time and with the
right patient … then you will be troubled and will work a lot
in order to get the etiology.
58. Diagnostic Testing
↑ High ESR lacks specificity:→
Drug Reaction }
Thrombophlebitis } may cause very high ESR
Nephrotic Syndrome }
Normal ESR significant inflammatory process is→ absent with
exception.
59. Diagnostic Testing
Laparoscopy
To visualize and biopsy the pathology in the abdomen
suggestive of:
e.g. Tuberculous peritonitis
Peritoneal carcinomatosis
Biopsy
Enlarged lymph node
Granulomatous disease (Tuberculosis)
Metastatic carcinoma
Others
61. Diagnostic Testing
Cultures
Blood
Obtain more than 3 blood cultures from separate venipunctures
over 24 hr period if you are suspecting inf. Endocarditis prior
antimicrobial use.
Incubate the blood for 4 weeks, to detect the presence of SBE &
Brucellosis
Sputum: For Tuberculosis
63. Management of FUO
Withhold therapy until the cause is found
Exceptions:
Neutropenic Fever
Unstable hospitalized patient
Corticosteroids in suspected Temporal Arteritis
HIV Patients
Notes de l'éditeur
However, Engeron76 studied 100 postoperative cardiac surgery patients and was unable to demonstrate a relationship between atelectasis and fever. Furthermore, when atelectasis is induced in experimental animals by ligation of a mainstem bronchus, fever does not occur.77 78 However, Kisala and coworkers79 demonstrated that IL-1 and TNF- levels of macrophage cultures from atelectatic lungs were significantly increased compared with the control lungs. The role of atelectasis as a cause of fever is unclear; however, atelectasis probably does not cause fever in the absence of pulmonary infection.
76. Engoren, M (1995) Lack of association between atelectasis and fever. Chest 107,81-84[Abstract]
77. Shields, RT (1949) Pathogenesis of postoperative pulmonary atelectasis an experimental study. Arch Surg 48,489-503
78. Lansing, AM (1963) Mechanism of fever in pulmonary atelectasis. Arch Surg 87,168-174[ISI]
79. Kisala, JM, Ayala, A, Stephan, RN, et al (1993) A model of pulmonary atelectasis in rats: activation of alveolar macrophage and cytokine release. Am J Physiol 264(3 Pt 2),R610-R614[Abstract/Free Full Text]