presentation about FUO

1. Approach to a patient with
fever of unknown origin
Dr. Adrija Hajra; 2nd year MD student; Internal Medicine; SSKM & IPGMER

2. Fever is a protective response to infection and injury. An elevated temperature
enhances the body’s innate defense mechanisms by making conditions less favorable
for infectious microorganisms to thrive.
Elevated body temperature decreases the levels of iron in the bloodstream,
thus inhibiting the growth of some microorganisms.
There are some microorganisms that are heat sensitive, and do not grow well at
elevated body temperature.

3. What is PUO
Originally defined in 1961 by Petersdorf and Beeson
Fever >38.3C on two occasions
Fever for more then three weeks
Uncertain diagnosis after one week in hospital

4. Fever of Unknown Origin - Definition
 1. Fever >38.3 degree C ( 101 degree F) on at least two occasions
 2. Illness duration of > or = 3 weeks
 3. No known immunocompromised state
 4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and
the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR)
and C-reactive protein (CRP) level; platelet count; leukocyte count and differential;
measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline
phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase，
creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis;
urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and
tuberculin skin test (TST) .

5. The answer will be A
 The commonest cause of PUO is:
a) A common disease presenting in an atypical way.
b) A rare disease presenting in atypical way.
c) A common disease presenting typically.
d) A rare disease presenting typically.

6. Infection accounts for about 20-25 % of cases of FUO in Western
countries; next in frequency are neoplasms and non infectious
inflammatory diseases.
Outside Western countries infection causes 43% cases
of FUO.
Up to 50% of these cases are due to Tuberculosis.
EPIDEMIOLOGY:

7. EPIDEMIOLOGY(GEOGRAPHY WISE)

8. A study on FUO patients in SKIMS, Srinagar(July 2010- Sept
2012):
n=91
Infection=40 cases, (32.26% Brucellosis)
Malignancy=11 cases
Inflammatory disease=11 cases
Miscellaneous=4 cases
Undiagnosed=25 cases
Mir T, Dhobi GN, Koul AN, Saleh T. Clinical profile of classical FUO. Caspian J Intern Med 2014; 5(1): 35-39.
Studies in India:

9. Although in India, approximately 80% of the population has close contact with domestic or wild
animals owing to their residence or occupation, carrying a risk for zoonotic diseases including
brucellosis, but only less than 10% of cases of FUO are attributed to brucellosis as evident from
various studies from India. This could be explained by either the disease is overlooked or
difficulty in correct diagnosis.
Kejariwal D et al from India observed his series of 100 cases of FUO, 53% were attributed to
tuberculosis, predominantly extra pulmonary. Sharma et al. reported 50% cases of FUO caused
by tuberculosis in northern India.
Kejariwal et al. and Ramamoorthy et al. estimated an incidence of 17% and 3.61% of
malignancy as a case of FUO, respectively.
Ramamoorthy K and Bang M. Pyrexia of unknown origin. CME 2004; pp; 385-390. Availible at: URL: http://appiindia.org/pdf/pg-med-2004/chapter-52. Accessed Nov 18,
2013. Pdf.
Kejariwal D, Sarkar N, Chakraborti SK, Agarwal V, Roy S. Pyrexia of Unknown Origin: A Prospective Study of 100 Cases. J Postgrad Med 2001; 47: 104-7.
Sharma BK, Kumari S, Varma SC, Sagar S, Singh S. Prolonged undiagnosed fever in North India. Trop Geogr Med 1992; 44: 32-6.

10. Four Proposed Categories of FUO
 Based on potential etiology of FUO
 All require temperature > 38.3C
 Categorization be especially helpful in organizing an “approach” to
patient evaluation
Classic
Nosocomial
Immune-deficient (neutropenic)
HIV-related

11. Classic Category of FUO
 Definition:
Duration > 3 weeks, evaluation of at least 3 outpatient visits or 3 days in-
hospital
 Common etiologies:
Infection, malignancy, CVD

12. Nosocomial Category of FUO
 Definition:
Hospitalization of at least 24 hrs with no fever on admission,
evaluation of at least 3 days

13. Common causes
This is commonly related to hospital associated factors such as,
 Surgery
 use of urinary catheter
 intravascular devices (i.e. "drip", pulmonary artery catheter)
 drugs (antibiotics induced Clostridium difficile colitis, and drug fever)
 immobilization (decubitus ulcers). Sinusitis in the intensive care unit is
associated with nasogastric and orotracheal tubes.
 deep-vein thrombophlebitis
 pulmonary embolism,
 transfusion reactions, acalculous cholecystitis
 alcohol/drug withdrawal
 adrenal insufficiency
 pancreatitis

14. IMMUNE DEFICIENT PUO
 Fever >38.0° C, >3 days duration, negative cultures after 48 hrs.
 Higher chance of atypical infections.
 Immunodeficiency can be seen in patients receiving chemotherapy
or in hematologic malignancies.
 Fever is concommittent with neutropenia (neutrophil <500/uL) or
impaired cell-mediated immunity. The lack of immune response
masks a potentially dangerous course.
 Infection is the most common cause

15. HIV-Associated Category of FUO
 Definition:
Duration of at least 4 weeks for outpatients and 3 days for
inpatients, HIV confirmed
 Etiologies:
Cytomegalovirus, MAC, Pneumocystis, drugs, Kaposi’s,
lymphoma

16. CAUSES:

17. Infection:
Bacterial (specific and non specific )
Fungal
Parasitic
Viral
Non infectious inflammatory:
Systemic rheumatic and autoimmune disease
Vasculitis
Granulomatous disease (Sarcoidosis)
Auto inflammatory syndromes
Neoplasm:
Hematologic malignancy
Solid tumors
Benign tumors

18. Miscellaneous:
ADEM
Atrial myxoma
Drug fever
Aortic dissection
Extrinsic allergic alveolitis
Metal fume fever
Pulmonary embolism
Ulcerative colitis
Sweet syndrome
Thrombosis
Thermoregulatory disorder:
Brain tumor
Encephalitis
Anhidrotic ectodermal dysplasia

20. Etiologies of FUO
 Infection
Tuberculosis: .. Disseminated
The single most common infection in most PUO series
except in children and elderly.
Usually extrapulmonary or miliary
Pulmonary TB in AIDS is often subtle (normal chest x-
rays → 15 – 30%).
PPD is (+ve) < 50% of TB with PUO.
Diagnosis often requires Bx of LN/Liver/Bone marrow.
Sputum smear (+) only 25%

21. Etiologies of FUO
Abscess:
Usually located in abdomen or pelvis.
Secondary to appendicitis or diverticulitis.
Amoebic liver abscess is one of the common causes
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.

22. Etiologies of FUO
 Bacterial Endocarditis
Culture remains negative in 5% 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
Mycoplasm/Chlamydia }
Fungal → usually sterile
Peripheral signs may not be detected.
Right-side Endocarditis → Lack murmurs → self antibiotics →
growth (-ve).

23. Etiologies of FUO
 Lymphoma:
Fever is a well-recognized manifestation.
Source of fever → production of cytokines.
Fever is a negative prognostic factor …
 Renal Cell Carcinoma (Adult)
20% → Fever
Microscopic hematuria/Erythromytosis

24. Etiologies of FUO
 Wilms Tumor (Children)
Peak incidence 2-3 years.
Abdominal mass but FEVER can be a presentation.
 Solid Tumor
Fever is rare except:
Secondaries to the liver
Ductal obstruction or perforation … like
cholangioacarcinoma or ampulla ca.
Lung carcinoma with obstruction and pneumonia.

25. Etiologies of FUO
 Still’s Disease Adult Onset
Age 16 – 33 yrs with (-ve) RF & ANA
Fever is high and spiking with Temp. up to 41.6oC
Fever is either intermittent or remittent … peaks typically
at night
Most patient seek medical attention within 2 weeks.
A distinctive evanescent macular or maculopapular rash is
typically present during the course of the illness.

26. Etiologies of FUO
Diagnosis is strictly a clinical one … RF is almost
uniformally negative.
Other features → myalgias, arthritis may appear after
weeks or months & leukocytosis (neutrophils),
hepatosplenomegaly & lymphadenopathy.
Very high serum ferritin … more than 2000

27. Etiologies of FUO
 Temporal Arteritis:
Very serious condition if not diagnosed early
… Very difficult to establish the etiology of fever if one
does not have the index of suspicion
Typically Caucasian but it occurs in others
Fever and malaise may be the only manifestation.
Headache is the most common.
Raised ESR is suggestive

28. Etiologies of FUO
 Polymyalgia Rheumatica:
Can cause fever, arthralgia, myalgia & ↑ ESR > 50.
Chronic muscle complaints → symmetrical pain and
stiffness that are typically worse at morning and affects
lumbar spine and large proximal muscles.
 Other vasculitides that cause FUO:
Polyarteritis nodosa
Wegener’s Granulomatosis
Mixed Cryoglobulinemia

29. Drug Fever
 Almost any drug can cause fever
PATHOGENESIS
 Contamination of the drug with a pyrogen or microorganism.
 Related to the pharmacologic action of the drug itself (e.g
amphotericin B).
 Allergic (hypersensitivity) reaction to the drug.

30.  Fever out of proportion to clinical picture
 Pattern of fever variable
 Associated findings:Rigor (43%), Myalgia (25%), Rash (18%),
Headache (18%)
 Leukocytosis (22%), Eosinophilia (22%), Serum sickness (fever,
swelling, rash, LN enlargement), Proteinuria, Abnormal liver
function test

31. Allopurinol
Carbamazepine
Cimetidine
Clofibrate
Erythromycin
Furosemide
Heparin
Hydralazine
Hydrochlorothiazide
Isoniazid
Minocycline
Nevirapine
Nitrofurantoin
Lamotrigine
Penicillin
Phenytoin
Procainamide
Quinidine
Sulfasalazine
Vancomycin
Agents commonly associated with drug-induced fever

32. Onset and duration:
 Onset: Typically occur 7 to 10 days (can be up to 21 days) after
initiation
 Usually resolves within 48 hrs after discontinuation of the drug
(depending on the half-life of the drug)

33. Endocrine causes for FUO
 Adrenal insuffiency
 Hashimotos encephalopathy
 Hypothalamic hypopituitarism
 Primary hyperparathyroidism
 Sub acute thyroiditis
 Hyperthyroidism
 Pheochromocytoma

34. EVALUATION

35. History
 Fever (Pattern, periodicity, how was it measured
associated symptoms such as sweating, vomiting, headaches etc.)
 Past medical and surgical history ( prosthesis in situ, cardiac illness, diabetes,
h/o transplant)
 Occupation, Travel
 Pets
 Contact with ticks, animals
 Diet (Drinking unpasteurised milk)
 History of addiction
 Sexual behaviour(any other high risk behaviour)
 Drug history
 Immunisation

36. Diagnostic Approach –
Physical Examination
The general appearance
The skin: rash, cutaneous findings of endocarditis
Perineum and feet
Spine,bones,joints,abdomen,thyroid
Digital rectal and pelvic examination
Lymphadenopathy
Cardiac examination
Repeated examination may be needed

37. Altered mentation—tuberculous meningitis, cryptococcal meningitis, carcinomatous
meningitis, brucellosis, typhoid fever, sarcoid meningitis
Arthritis or arthralgia—systemic lupus erythematosus, infective endocarditis, Lyme
disease, lymphogranuloma venereum, Whipple’s disease, brucellosis, inflammatory
bowel disease
Animal contact—brucellosis, toxoplasmosis, cat scratch disease, psittacosis,
leptospirosis, Q fever, rat bite fever
Cough—tuberculosis, Q fever, typhoid fever, sarcoidosis, Legionnaires’ disease
Conjunctival suffusion—leptospirosis, relapsing fever, Rocky Mountain spotted fever
Common signs and symptoms and associated causes of fever

38. Epistaxis—Wegener’s granulomatosis, relapsing fever, psittacosis
Epididymo-orchitis—tuberculosis, lymphoma, polyarteritis nodosa, brucellosis,
leptospirosis, infectious mononucleosis
Hepatomegaly—lymphoma, disseminated tuberculosis, metastatic carcinoma of liver,
alcoholic liver disease, hepatoma, relapsing fever, granulomatous hepatitis, Q fever,
typhoid fever, malaria, visceral leishmaniasis
Lymphadenopathy—lymphoma, cat scratch disease, tuberculosis, lymphomogranuloma
venereum, infectious mononucleosis, cytomegalovirus infection, toxoplasmosis, HIV
infection, brucellosis, Whipple’s disease, Kikuchi’s disease

39. Renal angle tenderness—perinephric abscess, chronic pyelonephritis
Splenomegaly—leukaemia, lymphoma, tuberculosis, brucellosis, sub acute
bacterial endocarditis, cytomegalovirus infection, Epstein-Barr virus
mononucleosis, rheumatoid arthritis, sarcoidosis, psittacosis, relapsing fever,
alcoholic liver disease, typhoid fever, Kikuchi’s disease
Subconjunctival hemorrhage—infective endocarditis, trichinosis, leptospirosis
Uveitis—tuberculosis, sarcoidosis, adult Still’s disease, systemic lupus
erythematosus, Behcet’s disease

40. Points to be rememberedduring evaluation of a patient with FUO :
 Previous case reports and history given by the patient should be
reviewed properly.
 Initial errors of omission may cause unnecessary investigations.
 Even when initial evaluation was thorough, patients often remember
new details when questioning is repeated.
 Conversely clinicians should not ignore previous test results and
should not repeat tests without considering how likely results are
to be different.

41. Clues to the diagnosis of factitious fever

42. Diagnostic Approach –
Laboratory Investigations
CBC, ESR,CRP
Routine chemistry including LFT,LDH,CPK
Renal function test
Urinalysis and microscopy
Stool for ova, cyst, parasite
Blood culture (including fungal culture)
Study of fluid from joint aspiration, pleural fluid,
Ascitic fluid, CSF, gastric aspirate

43. Typhoid Serology
HIV, Hepatitis, Dengue serology
CXR, sputum test
Tuberculin test, interferon gamma assay
USG abdomen
MP/MPDA, Microfilaria
Test for CMV, EBV, Q fever
ANA, ANCA, Rheumatoid factor

44. Abdominal CT
 Useful to look for abdominal lymphoma and abscess
 Diagnostic yield in case series 19%
 Clinical follow-up showed that only 1/32 patients with normal scans had an intra-abdominal cause
for FUO
Chest CT
Invaluable in identification of
small nodules, hilar or
mediastinal adenopathy.

45. Liver Biopsy:
Diagnostic yield 14%-17% regardless of whether abnormal physical exam or
liver enzymes exist
Complications in FUO from biopsy only 0.32% at most
Recommended
Temporal artery biopsy:
 Large studies comprised of elderly with FUO lacking
 Arteritis cause of FUO ~16% of patients
 Safe, recommended in elderly with FUO

46.  Other tissue diagnosis: Bone marrow, skin, pleura, lymph nodes,
intestine.
 (biopsy specimens should be evaluated by histopathologic
examination & cultured for bacteria, fungi, viruses, mycobacteria or
sent for PCR)
Splenic aspiration: visceral leishmaniasis
Bone marrow biopsy has a diagnostic yield up to 15%, most often
revealing hematologic malignancy, myelodysplasia, or tuberculosis, and
also identifying brucellosis, typhoid fever or visceral leishmaniasis.
Muscle biopsy and skin biopsy from rashes may confirm vasculitis.
Laparoscopy & abdominal exploration

47. Other investigations:
Lumbar puncture
Bone Tc-scan (osteomyelitis)
UGIE
Pulmonary angiogram
Ophthalmoscopy
Echocardiography

48. Recent studies have highlighted the usefulness of early use of FDG-PET
([18F] fluoro-2-deoxy-D-glucose positron emission tomography), which
may be useful in helping to pinpoint a source of fever.
Fluoro-2-deoxy-D-glucose is preferentially taken up by cells such as
tumor and inflammatory cells, in which glucose metabolism is high.
The diagnostic yield may be increased further by simultaneously using
FDG-PET with conventional computed tomography (CT). Several small
retrospective studies have shown sensitivities from 56% to100%,
specificities from 75% to 81%, and negative predictive values of 100%,
when a combination of CT and FDG-PET scanning is used.
Role of FDG-PET:

49. A high NPV has previously been reported for
FDG-PET/CT in the diagnosis of large vessel
vasculitis, with a sensitivity ranging between 77%
and 92% and specificity ranging between 89%
and 100%. 18F-FDG-PET/CT offers a useful
contribution to the diagnostic work-up of large
vessel vasculitis.
http://dx.doi.org/10.1016/j.ijid.2013.10.009

50. Nuclear scintigraphy, for example with 67Ga-citrate and111In labelled
leukocytes, is a much cheaper and more widely available imaging
technique that may perform a similar role in localizing pathology, though it
is more time consuming and less sensitive and specific than FDG-PET.
However, the probability of reaching a diagnosis was observed in 71% with
a sensitivity of 75% and specificity 83%. Leukocyte scintigraphy may be
helpful in diagnosing inflammatory and infectious conditions and rarely of
use in neoplasm.
Nuclear study:

51. History is crucial. Will help to narrow down
possible list of diseases.
Exposure: Duration, exact location, urban/rural,
type of accommodation
Timing: Consider incubation period and onset
of symptoms. 66% of dengue presents within
one week of return. 34% of hepA presents
within 6 weeks
Food history is important
Sexual history is important
Vaccine history
FOR TRAVELLERS

52. Evaluation
 Thick and Thin smears for malaria
 Blood count
 Renal profile
 Liver profile: hepatitis
 Coagulation screen
 CXR if respiratory symptoms

55. Treatment:55
 Limitation 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.
In general, empirical therapy has little or no role in cases of fever of unknown origin
(FUO).
Treatment should be directed toward the underlying cause, as needed,
once a diagnosis is made.

56. Empirical therapeutic trials with antibiotics, glucocorticoids, or
antituberculous agents should be avoided in FUO except when a
patient's condition is rapidly deteriorating after the aforementioned
diagnostic tests have failed to provide a definite diagnosis.
Empirical antibiotic therapy: Hemodynamic instability or neutropenia Good indication
Anti tuberculous therapy: If the skin test is positive
Granulomatous disease with anergy
Miliary tuberculosis
If the fever does not respond after 6 weeks Another diagnosis

57.  Colchicine is highly effective in preventing attacks of familial Mediterranean fever.
With colchicine treatment most patients show remarkable improvements in the
frequency and severity of subsequent febrile episodes within weeks to months.
 The response of adult onset Still’s disease to NSAIDS is dramatic in some cases.
 The effects of glucocorticoids on giant cell arteritis and polymyalgia rheumatica
are equally impressive.
 The ability of glucocorticoids to mask symptoms while permitting the spread
of infection dictates that their use should be avoided unless infectious diseases
have been ruled out and inflammatory disease is probable and is likely to be
debilitating or threatening.

58. Anakinra:
Interleukin (IL)1 is a key cytokine in local and systemic inflammation
and the febrile response.
The availability of specific IL-1-targeting agents has revealed a pathologic role of
IL-1 mediated inflammation in a growing list of diseases.
Anakinra, a recombinant form of the naturally occurring I L-1 receptor
antagonist ( lL-1Ra), blocks the activity of both IL-1α and IL-1ß.
Anakinra is extremely effective in the treatment of many autoinflammatory
syndromes, such as
familial Mediterranean fever，
cryopyrin-associated periodic syndrome，
tumor necrosis factor receptor-associated periodic syndrome，
hyper- lgD syndrome.

59. PROGNOSIS:
 FUO-related mortality rates have continuously declined over
recent decades.
 The majority of fevers are caused by treatable diseases.
 Studies have also shown that malignancy accounts for
most FUO-related deaths.
 Non Hodgkin's lymphoma carries a disproportionately high
death toll.
 In nonmalignant FUO, fatality rates are very low.
 The good outcome in patients without a diagnosis confirms
that potentially lethal occult diseases are very unusual.
 Empirical therapy with antibiotics, antituberculous agents, or
glucocorticoids is rarely required in stable patients.
 In less affluent regions, infectious diseases are still a major
problem.

60. CONCLUSION:
FUO is often a diagnostic dilemma.
Infections comprise ~30% of cases.
Diagnostic approach should occur in a step-wise fashion
Patients that remain undiagnosed generally have a good
prognosis.
18F-FDG-PET/CT has an incremental diagnostic value in the
diagnosis and management of FUO. In the future, 18F-FDG-
PET/CT may well be included in the initial diagnostic work-up for
the investigation of the etiology of FUO.